bims-tuinly 2025-07-06 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–07–06
thirty papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Local single-dose radiation improves adoptive cell therapy with tumor infiltrating lymphocytes.
Assessment of established prognostic factors and artificial intelligence-based evaluation of tumor-infiltrating lymphocytes in oral tongue squamous cell carcinoma.
Tumor Infiltrating Lymphocytes in Breast Cancer: A Narrative Review with Focus on Analytic Validity, Clinical Validity, and Clinical Utility.
The prognostic significance of desmoplastic reaction, tumor budding and tumor-infiltrating lymphocytes in esophageal squamous cell carcinomas.
Deep learning-based quantification of tumor-infiltrating lymphocytes as a prognostic indicator in nasopharyngeal carcinoma: multicohort findings.
Pathologist-Read vs AI-Driven Assessment of Tumor-Infiltrating Lymphocytes in Melanoma.
PML localization in tumor associated macrophages as a prognostic marker in triple negative breast cancer.
Tumor-infiltrating lymphocyte therapies in gastrointestinal cancer.
The distribution characteristics of PD-1 pathway-related immune cells in esophageal cancer tissue and their prognostic significance.
Human cancer-targeted immunity via transgenic hematopoietic stem cell progeny.
A Study on Cancer-Associated Fibroblast Using Alpha-Smooth Muscle Actin Immunohistochemistry in Oral Squamous Cell Carcinoma.
Nivolumab and Ipilimumab Combination Treatment in Advanced Ovarian and Endometrial Clear Cell Cancers: A Nonrandomized Clinical Trial.
Prediction of Tumor-infiltrating Lymphocytes in Triple-negative and HER2-positive Breast Cancer Using Multi-modality Ultrasound and MRI: A Single-institution Retrospective Study.
Evaluation of a microfluidic chip-based cell sorter in clinical manufacturing processes to deplete or isolate CD4 regulatory T cells.
High matrix metalloproteinase-2 expression predicts poor prognosis of colon adenocarcinoma and is associated with PD-L1 expression and lymphocyte infiltration.
Inhibitory Immune Checkpoints beyond Programmed Cell Death Ligand 1 in Merkel Cell Carcinoma: Abundant Expression of TIGIT Independent of the Presence of Merkel Cell Polyoma Virus.
Radiation therapy results in preferential tumor antigen-specific lymphodepletion in head and neck cancer.
The future belongs to those who believe in multiplex CAR T engineering.
Different tumour-resident memory T-cell subsets regulate responses to anti-PD-1 and anti-CTLA-4 cancer immunotherapies.
Stromal tumor infiltrating lymphocytes and TNBC-DX provide complementary prognostic information in triple-negative breast cancer.
Extratumoral Signs of Malignant Nonspiculate and Noncalcified Masses on Mammography: Are They Associated With Prognostic Factors in Breast Cancer?
REPLY: The Assessment Approach of Frailty May Influence Its Prognostic Impact Amidst Clinical Trials.
Tumor site influences efficacy of MEKi and immunotherapy combinations in pre-clinical model of cholangiocarcinoma.
Bispecific targeting of 4-1BB and CCR8 boosts antitumor immunity via Ti-Treg depletion and CD8+ activation.
Tumor site-directed A1R expression enhances CAR T cell function and improves efficacy against solid tumors.
Comments on "Early Activation of Lung CD8+ T Cells After Immunization with Live Plasmodium berghei Malaria Sporozites".
Cardiolipin-mimic lipid nanoparticles without antibody modification delivered senolytic in vivo CAR-T therapy for inflamm-aging.
Optimized lentiviral backbone induces robust and diverse T cell immunity against neoantigens to counteract tumor heterogeneity.
Prognostic value of the StAN score in elderly small cell lung cancer.
Comprehensive risk score of the E-PASS scoring system serves a prognostic indicator for patients after neoadjuvant therapy and curative esophageal cancer surgery: a multicenter retrospective study.

Int J Radiat Oncol Biol Phys. 2025 Jun 27. pii: S0360-3016(25)04498-0. [Epub ahead of print]

Local single-dose radiation improves adoptive cell therapy with tumor infiltrating lymphocytes.

N Obertopp, R A Bekker, G D Grass, T Zelenka, A Thomas, M Potez, J Ali, J Blauvelt, A M Hall, M S Hall, C H Chung, H Enderling, S Pilon-Thomas.

INTRODUCTION: The potential for radiation therapy (RT) to enhance adoptive cell therapy (ACT) with tumor-reactive T cells has not been fully explored. This study evaluated combining RT with ACT, applying RT at two critical time points: (1) before tumor resection to improve TIL ex vivo expansion of tumor infiltrating lymphocytes (TIL) and (2) on the day of ACT using antigen-specific T cells to enhance T-cell infiltration after transfer.
METHODS: Using a murine HPV+ head and neck squamous cell carcinoma model, we administered single-dose RT (8 Gy x 1) five days before tumor resection. RNA sequencing was performed to measure chemokine expression post-RT. Tumor fragments were cultured in IL-2 for TIL expansion, and TIL reactivity was assessed through cytokine production assays. Tumor-bearing mice were treated with ACT with TIL expanded from untreated or RT-treated tumors. In additional experiments, we assessed whether RT given in combination with ACT could improve infiltration of T cells and anti-tumor activity.
RESULTS: RT preconditioning significantly enhanced ex vivo TIL expansion (96% vs. 74%, p<0.05) and increased TNFα production (p=0.03), indicating improved reactivity. RT also significantly increased the expansion of TNFα+GzmB+ CD8+ TILs (p=0.02), suggesting enhanced polyfunctionality within a cytotoxic subset. RNA sequencing revealed upregulation of key chemokines (e.g., CCL21, CXCL10) and their receptors (CCR7, CXCR4), supporting enhanced TIL recruitment. ACT with TIL from RT-preconditioned tumors demonstrated superior tumor control, with 50% of mice achieving complete tumor regression (CR) compared to 12.5% in controls. RT on the day of ACT increased T-cell infiltration into tumor and improved tumor rejection compared to mice receiving either ACT or RT alone.
CONCLUSIONS: RT at two distinct time points-before tumor resection to enhance TIL expansion and on the day of ACT to boost T-cell infiltration-significantly improves TIL the efficacy of ACT. These findings highlight the potential for combining RT with ACT to enhance therapeutic outcomes in metastatic disease.

DOI: https://doi.org/10.1016/j.ijrobp.2025.06.3856
Oral Oncol. 2025 Jul 02. pii: S1368-8375(25)00277-5. [Epub ahead of print]167 107448

Assessment of established prognostic factors and artificial intelligence-based evaluation of tumor-infiltrating lymphocytes in oral tongue squamous cell carcinoma.

Jongwon Lee, Ming Fan, Donghyeok Jo, JungBok Lee, Joon Seon Song, Hee Jin Lee, Seung-Ho Choi, Soon Yuhl Nam, Yoon Se Lee, Dong-Joo Kim, Kyung-Ja Cho.

   BACKGROUND: Traditional risk assessment for tongue cancer relies on clinicopathological parameters. Although tumor-infiltrating lymphocytes (TILs) are promising prognostic markers, their evaluation lacks standardization. This study aimed to validate established prognostic factors and introduce an artificial intelligence (AI)-based TIL assessment method.
METHODS: We analyzed 139 tongue cancer cases from a single institution (2010-2017) to establish prognostic factors and developed an AI model for TIL quantification. Clinicopathological characteristics including AI- and manually assessed TILs were evaluated.
RESULTS: The AI-assessed stromal TIL ratio exerted protective effects across all stages and demonstrated superior discriminative capability compared to manual evaluation (C-index: 0.649 vs. 0.604 for overall survival [OS]), with substantial inter-method agreement (Intraclass Correlation Coefficient = 0.796). In the multivariate analysis, a statistical model incorporating the lymph node ratio, AI-assessed stromal TIL ratio, depth of invasion grade, perineural invasion, lymphovascular invasion, and a close surgical resection margin (<5 mm) showed superior prognostic performance, with excellent discriminative power (OS area under the curve [AUC]: 0.851; recurrence-free survival [AUC]: 0.826). Stage-specific analysis revealed that advanced-stage patients were significantly affected by adverse factors and stromal TIL levels, whereas early stage patients showed trends but no statistically significant associations.
CONCLUSIONS: AI-based stromal TIL assessment outperformed manual TIL assessment as a prognostic marker. This AI approach robustly predicts survival when combined with factors such as the lymph node ratio and a close resection margin status (<5 mm). Our findings may enhance risk stratification, particularly in advanced-stage disease.

Keywords:  Artificial intelligence; Prognosis; Risk factor; Tongue cancer; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.oraloncology.2025.107448
Hum Pathol. 2025 Jul 02. pii: S0046-8177(25)00153-4. [Epub ahead of print] 105866

Tumor Infiltrating Lymphocytes in Breast Cancer: A Narrative Review with Focus on Analytic Validity, Clinical Validity, and Clinical Utility.

Brian S Finkelman, Huina Zhang, David G Hicks, David L Rimm, Bradley M Turner.

  Since Dr. Stephen Paget first proposed the "seed and soil" hypothesis in 1889, the tumor microenvironment has been recognized as a crucial component of tumor growth, progression, and metastasis. Tumor-infiltrating lymphocytes (TILs) are an important part of the tumor microenvironment, as well as an important prognostic and predictive biomarker for many cancers. This narrative review aims to summarize the current literature on the analytic validity, clinical validity, and clinical utility of TILs in breast cancer, including discussion of all major clinical subtypes. We summarize the current recommendations of the International Immuno-Oncology Biomarker Working Group on Breast Cancer for pathologist assessment and reporting of TILs, the state of the evidence justifying their usefulness as a biomarker in breast cancer, particularly for triple-negative and HER2+ breast cancer, as well as ongoing challenges and areas of future development, such as automated TIL scoring algorithms. Based on currently available evidence as well as ongoing clinical trials, we expect that TILs will increasingly become a cost-effective, easily available, and widely utilized biomarker in breast cancer, helping to guide treatment selection and de-escalation for many patients.

Keywords:  TILs; TME; TNBC; breast cancer; lymphocytes

DOI:  https://doi.org/10.1016/j.humpath.2025.105866
BMC Gastroenterol. 2025 Jul 01. 25(1): 476

The prognostic significance of desmoplastic reaction, tumor budding and tumor-infiltrating lymphocytes in esophageal squamous cell carcinomas.

Ozlem Ceren Gunizi, Busra Altunay, Selin Didar Turgut, Gulsum Ozlem Elpek.

   BACKGROUND: Recent research has demonstrated the importance of the tumor microenvironment (TME) in the behavior of solid tumors. Numerous discoveries suggest that tumor progression in a variety of malignancies, including those of the gastrointestinal tract, may be predicted by pathological evaluation of the desmoplastic reaction (DR), tumor budding (TB) and tumor-infiltrating lymphocytes (TIL). While some studies have demonstrated the prognostic impact of TIL in patients with squamous cell carcinoma of the esophagus (ESCC), the data have not reached agreement. Furthermore, few studies have investigated the relationship of DR and TB with disease progression. The relationships between DR, TB and TIL in these tumors remain to be investigated. Therefore, this study was undertaken to explore the relationships between DR, TB and TIL and histopathological parameters related to tumor behavior and assess their prognostic role in predicting survival in patients with ESCC.
METHODS: The retrospective case series included 98 patients diagnosed with ESCC. DR was assessed on the basis of the maturation of the tumor stroma. TB was evaluated according to the International Tumor Budding Conference (ITBCC) criteria. A semiquantitative method with a 5% threshold value was used to evaluate TIL.
RESULTS: A significant correlation was identified between DR and sex (p = 0.023) and between DR and depth of invasion (T) (p = 0.006). TB and TIL were correlated with T (p < 0.001 and p = 0.002), lymph node metastasis (LNM) (p = 0.006 and p = 0.018), tumor stage (p < 0.001) and p = 0.003). Although DR was significantly positively correlated with TB (p < 0.001), no correlation was detected with TIL. A negative correlation between TIL and TB was also observed (p = 0.04). The results of the univariate analysis revealed significant correlations between poor survival rates and T (p < 0.001), LNM (p = 0.002), stage (p < 0.001), DR (p < 0.001), TB (p < 0.001), and TIL (p = 0.009). The multivariate analysis revealed that DR (p < 0.001), TB (p < 0.001), and T (p < 0.001) were independent prognostic factors.
CONCLUSION: Our study emphasized that the assessment of DR and TB can be used to categorize individuals with ESCC for therapy and prognosis. Further research is needed to clarify the prognostic roles of TIL and their subtypes in ESCC and how they are associated with DR, depending on their association with TB.

Keywords:  Desmoplastic reaction; Esophageal squamous cell carcinoma; Tumor budding; Tumor infiltrated lymphocytes

DOI:  https://doi.org/10.1186/s12876-025-03984-y
ESMO Open. 2025 Jul 03. pii: S2059-7029(25)01363-8. [Epub ahead of print]10(7): 105494

Deep learning-based quantification of tumor-infiltrating lymphocytes as a prognostic indicator in nasopharyngeal carcinoma: multicohort findings.

T Lu, F Xie, Y Hu, S Zhan, F Zhong, J Chen, J Pan, X Gong, Z Liu, C Huang, C Xie, Q Guo, M L K Chua, J Li.

   BACKGROUND: Nasopharyngeal carcinoma (NPC) features a tumor-immune microenvironment rich in tumor-infiltrating lymphocytes (TILs), important for prognosis but labor-intensive to quantify. This study evaluates a deep learning model to quantify TILs (TILDL) in hematoxylin and eosin (H&E)-stained whole-slide images (WSIs) of NPC and explores the association of TILDL percentage with patient outcomes and response to immune checkpoint blockade (ICB).
METHODS: We retrospectively analyzed 435 nonmetastatic NPC patients from two centers, divided into a training cohort (n = 220) and a validation cohort (n = 215). An additional cohort of de novo metastatic NPC patients receiving ICB therapy (n = 63) was included. The deep learning model calculated TILDL percentages from H&E-stained WSIs. Correlations between TILDL percentages and immunohistochemistry (IHC)-derived TIL densities were assessed. Survival analyses evaluated their prognostic significance.
RESULTS: TILDL percentages showed strong correlations with IHC-derived TIL densities (CD3+ T cells R = 0.46, CD8+ T cells R = 0.33, CD20+ B cells R = 0.57; all P < 0.001). Higher TILDL percentages (median ≥45.7%) were associated with better 5-year disease-free survival (DFS) and overall survival (OS) in both training (DFS: 80.6% versus 62.5%, P = 0.016; OS: 84.4% versus 71.8%, P = 0.025) and validation cohorts (DFS: 87.3% versus 74.3%, P = 0.016; OS: 93.7% versus 82.6%, P = 0.010). In the ICB-treated metastatic cohort, higher TILDL percentages predicted better 3-year progression-free survival (PFS: 40.5% versus 25.0%, P = 0.022). Multivariate analyses confirmed TILDL percentage as an independent prognostic factor in both settings.
CONCLUSIONS: The TILDL percentage derived from H&E-stained WSIs effectively stratifies risk in nonmetastatic NPC and may serve as a biomarker in metastatic NPC treated with ICB, aiding in patient selection for individualized treatment.

Keywords:  deep learning; digital pathology images; nasopharyngeal carcinoma; prognosis; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.esmoop.2025.105494
JAMA Netw Open. 2025 Jul 01. 8(7): e2518906

Pathologist-Read vs AI-Driven Assessment of Tumor-Infiltrating Lymphocytes in Melanoma.

Thazin N Aung, Matthew Liu, David Su, Saba Shafi, Ceren Boyaci, Sanna Steen, Nikolaos Tsiknakis, Joan Martinez Vidal, Nigel Maher, Goran Micevic, Samuel X Tan, Matthew D Vesely, Saeed Nourmohammadi, Yalai Bai, Dijana Djureinovic, Pok Fai Wong, Katherine Bates, Nay N N Chan, Niki Gavirelatou, Mengni He, Sneha Burela, Robert Barna, Martina Bosic, Konstantin Bräutigam, Irineu Illabochaca, Zhou Chenhao, Joao Gama, Bianca Kreis, Reka Mohacsi, Nir Pillar, Joao Pinto, Christos Poulios, Maria Angeliki Toli, Evangelos Tzoras, Yadriel Bracero, Francesca Bosisio, Gábor Cserni, Alis Dema, Francesco Fortarezza, Mercedes Solorzano Gonzalez, Irene Gullo, Francisco Javier Queipo Gutiérrez, Ezgi Hacihasanoglu, Viktor Jovic, Bianca Lazar, Maria Olinca, Christina Neppl, Rui Caetano Oliveira, Federica Pezzuto, Daniel Gomes Pinto, Vanda Plotar, Ovidiu Pop, Tilman Rau, Kristijan Skok, Wenwen Sun, Ezgi Dicle Serbes, Wiebke Solass, Olga Stanowska, Marcell Szasz, Krzysztof Szymonski, Franziska Thimm, Danielle Vignati, Alon Vigdorovits, Victor Prieto, Tobias Sinnberg, James Wilmott, Shawn Cowper, Jonathan Warrell, Yvonne Saenger, Johan Hartman, Jasmine Plummer, Iman Osman, David L Rimm, Balazs Acs.

Importance: Tumor-infiltrating lymphocytes (TILs) are a provocative biomarker in melanoma, influencing diagnosis, prognosis, and immunotherapy outcomes; however, traditional pathologist-read TIL assessment on hematoxylin and eosin-stained slides is prone to interobserver variability, leading to inconsistent clinical decisions. Therefore, development of newer TIL scoring approaches that produce more reliable and consistent readouts is important.
Objective: To evaluate the analytical and clinical validity of a machine learning algorithm for TIL quantification in melanoma compared with traditional pathologist-read methods.
Design, Setting, and Participants: This multioperator, global, multi-institutional prognostic study compared TIL scoring reproducibility between traditional pathologist-read methods and an artificial intelligence (AI)-driven approach. The study was conducted using retrospective cohorts of patients with melanoma between January 2022 and June 2023 across 45 institutions, with tissue evaluated by participants from academic, clinical, and research institutions. Participants were selected to ensure diverse expertise and professional backgrounds.
Main Outcomes and Measures: Intraclass correlation coefficient (ICC) values were calculated for the manual and AI-assisted arms using log-transformed data. Kendall W values were calculated for Clark scores (brisk = 3, nonbrisk = 2, and sparse = 1). Reliabilities of ICC and W values were classified as moderate (0.40-0.60), good (0.61-0.80), or excellent (>0.80). AI TIL measurements were dichotomized using the 16.6 and median cutoffs. Univariable and multivariable Cox regression analyses assessed the prognostic value of TIL scores adjusted for clinicopathologic variables.
Results: There were 111 patients with melanoma in the independent testing cohort (median [range] age at diagnosis, 61.0 [25.0-87.0] years; 56 [50.5%] male) who contributed melanoma whole tissue sections. A total of 98 participants evaluated TILs on 60 hematoxylin and eosin-stained melanoma tissue sections. All 40 participants in the manual arm were pathologists, while the AI-assisted arm included 11 pathologists and 47 nonpathologists (scientists). The AI algorithm demonstrated superior reproducibility, with ICCs higher than 0.90 for all machine learning TIL variables, significantly outperforming manual assessments (ICC, 0.61 for AI-derived stromal TILs vs Kendall W, 0.44 for manual Clark TIL scoring). AI-based TIL scores showed prognostic associations with patient outcomes (n = 111) using the median cutoff approach with a hazard ratio (HR) of 0.45 (95% CI, 0.26-0.80; P = .005), and using the cutoff of 16.6, with an HR of 0.56 (95% CI, 0.32-0.98; P = .04).
Conclusions and Relevance: In this prognostic study of TIL quantification in melanoma, the AI algorithm demonstrated superior reproducibility and prognostic associations compared with traditional methods. Although the retrospective nature of the cohorts limits demonstration of clinical utility, the publicly available dataset and open-source AI tool offer a foundation for future validation and integration into melanoma management.

DOI: https://doi.org/10.1001/jamanetworkopen.2025.18906
Sci Rep. 2025 Jul 01. 15(1): 22054

PML localization in tumor associated macrophages as a prognostic marker in triple negative breast cancer.

Bianca Vezzani, Sonia Missiroli, Massimo Pedriali, Patrizia Querzoli, Iva Maestri, Paolo Carcoforo, Giovanni Lanza, Roberta Gafà, Paolo Pinton, Carlotta Giorgi.

  Triple-negative breast cancer (TNBC) is a particularly aggressive and metastatic subtype, characterized by the absence of estrogen, progesterone, and human epidermal growth factor 2 receptors. Outcomes for TNBC patients vary widely, suggesting this classification encompasses different cancers with distinct histological, genomic, and immunological profiles, leading to variable prognoses. The tumor microenvironment, particularly the expression and localization of promyelocytic leukemia protein (PML) in tumor-associated macrophages (TAMs), can influence patient outcomes by modulating inflammation. The beneficial prognostic role of increased tumor-infiltrating lymphocytes (TILs) in TNBC is well-established. In this retrospective study, we found that PML expression in tumor cells is inversely related to the presence of TILs and is associated with poorer outcomes. Patients with disease recurrence exhibited higher levels of TAMs with predominantly nuclear-localized PML, in contrast to patients who showed complete recovery. The accumulation of PML in the nucleus reduces its presence at ER-mitochondria contact sites, impairing its interaction with the NLRP3 inflammasome and leading to increased IL-1β secretion. This promotes a pro-inflammatory tumor microenvironment as seen in patients with adverse outcomes. Our findings suggest that both PML expression in cancer cells and its localization in TAMs can serve as additional prognostic factors, highlighting the potential of PML as a therapeutic target in TNBC.

Keywords:  Breast cancer; PML; Prognostic markers; Triple negative breast cancer; Tumor-associated macrophages; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1038/s41598-025-01671-2
Nat Cancer. 2025 Jul 04.

Tumor-infiltrating lymphocyte therapies in gastrointestinal cancer.

Vincenzo Giacco.

DOI: https://doi.org/10.1038/s43018-025-01020-2
PLoS One. 2025 ;20(6): e0325349

The distribution characteristics of PD-1 pathway-related immune cells in esophageal cancer tissue and their prognostic significance.

Dehua Kong, Chunyan Gao, Yang Yu, Lu Yang, Ji Ma, Shimin Tang, Ying Mao, Yong Li, Na Li.

OBJECTIVE: This study aims to elucidate the distribution patterns of immune cells associated with the programmed cell death protein 1 (PD-1) pathway within esophageal cancer (EC) tissues and to determine their correlation with patient prognosis.
METHODS: We included tissue samples from 236 EC patients who had undergone surgery at our institution between January 2016 and January 2021. This study examined the correlation between six immunohistochemical markers and the clinical profiles of these patients. Survival analysis was performed using the Kaplan-Meier method and the LOG-rank test to evaluate the impact of immunohistochemical marker expression on patient survival. A clinical predictive model was developed and validated for prognostic assessment.
RESULTS: Expression levels of PD-1, PD-L1, FOXP3, and CD25 were found to be positively associated with the depth of tumor invasion and lymph node metastasis (P < 0.05). In contrast, CD4 and CD8 expression levels were inversely related to these parameters (P < 0.05). High expression of PD-1, PD-L1, FOXP3, and CD25, along with lymph node metastasis, were identified as independent prognostic risk factors (P < 0.05). Patients with low expression of PD-1, PD-L1, FOXP3, CD25, and high expression of CD4 and CD8 exhibited improved three-year survival rates (P < 0.001). The predictive model, based on these factors, demonstrated high discrimination and accuracy.
CONCLUSION: A prognostic model incorporating the expression levels of PD-1, PD-L1, FOXP3, CD25, and lymphocyte infiltration offers robust predictive validity for the prognosis of EC patients.

DOI: https://doi.org/10.1371/journal.pone.0325349
Nat Commun. 2025 Jul 01. 16(1): 5599

Human cancer-targeted immunity via transgenic hematopoietic stem cell progeny.

Theodore S Nowicki, Nataly Naser Al Deen, Cole W Peters, Begoña Comin-Anduix, Egmidio Medina, Cristina Puig-Saus, Ignacio Baselga Carretero, Paula Kaplan-Lefko, Mignonette H Macabali, Ivan Perez Garcilazo, Daniel Chen, Jia Pang, Beata Berent-Maoz, Salem Haile, Jonathan Rodriguez, Moe Kawakami, Conner K Kidd, Ameya Champhekar, Giuseppe Carlucci, Agustin Vega-Crespo, Bartosz Chmielowski, Arun Singh, Noah Federman, Gary M Schiller, Sarah J Larson, Martin Allen-Auerbach, Alexandra M Klomhaus, Jerome Zack, David Baltimore, Lili Yang, Donald B Kohn, Owen N Witte, Antoni Ribas.

Adoptive transfer of genetically engineered T cells expressing a tumor-antigen-specific transgenic T cell receptor (TCR) can result in clinical responses in a variety of malignancies. However, these responses are frequently short-lived, and patients typically relapse within several months. This phenomenon is largely due to poor persistence of the transgenic T cells, as well as a progressive loss of their functionality and terminal differentiation in vivo. This underscores the need for cell therapy approaches able to sustain the initial antitumor efficacy and lead to long-term antitumor efficacy. Herein, we report the use of tandem cell therapies involving autologous T cells and hematopoietic stem cells engineered to express the NY-ESO-1 TCR for the treatment of solid tumors in a first-in-human phase I clinical trial (NCT03240861). This therapy is shown to be safe, feasible, and leads to initial tumor regression activity. T cell progeny from the HSC progenitors is shown to provide circulating transgenic NY-ESO-1 TCR-T cells, which display tumor-antigen-specific antitumor functionality, without any evidence of anergy or exhaustion. These results demonstrate the utility of transgenic HSCs to generate a self-renewing source of tumor-specific cellular immunotherapy in human participants. Clinicaltrials.gov: NCT NCT03240861.

DOI: https://doi.org/10.1038/s41467-025-60816-z
Cureus. 2025 May;17(5): e85027

A Study on Cancer-Associated Fibroblast Using Alpha-Smooth Muscle Actin Immunohistochemistry in Oral Squamous Cell Carcinoma.

Ambika Kunhikannan, T N Suresh, S M Azeem Mohiyuddin.

  Background Oral squamous cell carcinoma (OSCC) represents a significant global health burden with complex pathophysiology involving tumor microenvironment interactions. The tumor stroma, particularly cancer-associated fibroblasts (CAFs), plays a crucial role in tumor advancement, invasion, and metastasis. CAFs, identified by alpha-smooth muscle actin (α-SMA) expression, influence tumor behavior through extracellular matrix remodelling and pro-tumorigenic signalling. Despite emerging evidence of their prognostic significance, the relationship between CAF expression patterns and clinicopathological parameters in OSCC remains inadequately characterized. Objectives This study aimed to detect CAFs using α-SMA immunohistochemistry in OSCC and evaluate their association with LNM and pTNM staging, potentially identifying new prognostic markers for clinical management. Methodology This laboratory-based analytical study was conducted between September 2022 and December 2023. Histopathologically confirmed OSCC cases (n=88) treated by composite resection and cervical lymph node dissection were included, excluding recurrent cases, patients who received neoadjuvant chemotherapy, and second primary cancers. H&E slides were reviewed for LNM and pTNM staging. Immunohistochemical staining for α-SMA was performed on 4 μm formalin-fixed paraffin-embedded tissue sections using heat-induced antigen retrieval, followed by incubation with primary antibody and horseradish peroxidase (HRP)-conjugated secondary antibody. CAF expression was quantified using Kellermann et al.'s scoring system (Score 1 is <1%, Score 2 is between 1% and 50%, and Score 3 is >50% stained cells) and categorized by distribution pattern (focal, network, or spindle). Additional parameters assessed included tumor-stroma ratio (TSR), worst pattern of invasion (WPOI), tumor budding (TB), and tumor-infiltrating lymphocytes (TILs). Results The study population comprised 88 patients (69.3% female, 30.7% male) (average age: 56.97 years). The buccal mucosa represented the most frequent site (50%), with well-differentiated tumors predominating (80.7%). Pathological staging revealed Stage IVA as the most prevalent (33%), followed by Stage III (31.8%). Regarding CAF expression, Score 3 (abundant CAFs) was observed in 55.7% of cases, Score 2 in 40.9%, and Score 1 in only 3.4%. Network pattern CAF distribution predominated (38.6%), with equal representation of focal and spindle configurations (30.7% each). Statistical analysis revealed no significant association between CAF scores and LNM (p=0.758); however, CAF distribution patterns demonstrated a statistically significant association with pTNM staging (χ²=26.716; p=0.001), with advanced stages showing a distinct pattern shift toward network and spindle arrangements. Notably, significant correlations were observed between TSR and CAF score (p<0.0001), TB and CAF score (p=0.021), and TB and LNM (p=0.047). More aggressive invasion patterns demonstrated higher CAF scores and increased TB intensity. Conclusion While CAF scores alone did not predict LNM, CAF architectural patterns demonstrated significant associations with pathological staging in OSCC. The correlations between CAF expression, TB, and invasion patterns suggest that CAF distribution may serve as a valuable prognostic indicator. These findings highlight the potential of CAF architectural evaluation as an adjunctive histopathological parameter for risk stratification in OSCC patients.

Keywords:  alpha-smooth muscle actin; cancer-associated fibroblasts; lymph node metastasis; oral squamous cell carcinoma; tumor budding; tumor microenvironment; tumor-stroma ratio

DOI:  https://doi.org/10.7759/cureus.85027
JAMA Oncol. 2025 Jul 03.

Nivolumab and Ipilimumab Combination Treatment in Advanced Ovarian and Endometrial Clear Cell Cancers: A Nonrandomized Clinical Trial.

Bo Gao, Matteo S Carlino, Michael Michael, Craig Underhill, Henry Marshall, Ashray Gunjur, Jane So, Damien Kee, Yoland Antill, Wei-Sen Lam, Howard Chan, Rosemary Harrup, Anne Hamilton, John Grady, Mandy Ballinger, Elnaz Tavancheh, Won-Hee Yoon, Jodie Palmer, David Thomas, Kylie Wilkie, Jonathan Cebon, Oliver Klein.

Importance: Gynecological clear cell cancers (CCCs) are aggressive malignant neoplasms with low response rate to chemotherapy. The treatment of patients with metastatic disease remains an area of significant unmet need.
Objective: To evaluate the efficacy of combined anti-programmed cell death 1 protein (PD-1)/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade using nivolumab and ipilimumab in advanced gynecological CCCs.
Design, Setting, and Participants: The MoST-CIRCUIT prospective multicenter phase 2 nonrandomized clinical trial included patients with advanced selected rare cancers. Patients with advanced clear cell ovarian cancer (CCOC)/clear cell endometrial cancer (CCEC) with a maximum of 1 course of prior systemic therapy were enrolled from August 2021 to February 2024 across 17 Australian and New Zealand sites.
Interventions: Patients received nivolumab, 3 mg/kg, and ipilimumab, 1 mg/kg, every 3 weeks for 4 doses followed by nivolumab, 480 mg, every 4 weeks for 96 weeks until disease progression or the development of unacceptable toxic effects.
Main Outcomes and Measures: Coprimary end points were objective response rate (ORR) and 6-month progression-free survival (PFS) as assessed by RECIST version 1.1 criteria, with the secondary end points being median overall survival, PFS, and treatment-related toxic effects.
Results: Of 28 included patients, the median (range) age was 55 (34-77) years. A total of 24 had CCOC and 4 had CCEC; 19 (68%) had a previous course of therapy. Overall ORR was 54% (95% CI, 35-71), with 3 (12%) with complete response and 12 (42%) with partial response; the ORR was 55% (95% CI, 35-73) in the CCOC group and 50% (95% CI, 9-91) in the CCEC group. The median duration of response has not been reached, with all responses ongoing. The 6-month PFS was 58% (95% CI, 39-74), and the median overall survival has not been reached. A total of 9 patients (35%) experienced a grade 3 or 4 immune-related adverse event, and a grade 5 myocarditis occurred in 1 patient.
Conclusions and Relevance: In this nonrandomized clinical trial, immunotherapy using combined anti-PD-1/CTLA-4 blockade demonstrated encouraging activity with a high rate of durable responses in patients with advanced gynecological CCCs. This regimen should be further investigated in this patient population with unmet medical need.
Trial Registration: ClinicalTrials.gov Identifier: NCT04969887.

DOI: https://doi.org/10.1001/jamaoncol.2025.1916
Br J Radiol. 2025 Jul 01. pii: tqaf146. [Epub ahead of print]

Prediction of Tumor-infiltrating Lymphocytes in Triple-negative and HER2-positive Breast Cancer Using Multi-modality Ultrasound and MRI: A Single-institution Retrospective Study.

Manqi Zhang, Li Gong, Mengjun Cai, Danyan Li, Jiong Shi, Yu Du, Pengli Yu.

   OBJECTIVE: To explore the potential of noninvasive imaging techniques in predicting tumour-Infiltrating lymphocytes (TILs) status in triple-negative (TN) and HER-2 positive breast cancers.
METHODS: Between April 2018 and November 2023, a total of 432 eligible TN and HER-2 positive breast cancers who underwent ultrasound (US) and magnetic resonance imaging (MRI) were retrospectively enrolled in this study. US and MRI variables were collected from the workstation. Fraction of TILs was determined histologically based on the proportion of lymphocytes infiltrated areas. A cutoff of 20% was established to distinguish between low and high levels of TILs. Predictive factors associated with high-TILs were identified using logistic regression analysis and a nomogram was developed. The diagnostic performance of the nomogram was evaluated.
RESULTS: A total of 432 patients with TN and HER2-positive breast cancer were evaluated, among which 228 patients (52.7%) exhibited high levels of TILs. Oval/round shape (odds ratio, [OR], 0.148; p = 0.001), circumscribed margin (OR, 0.174; p = 0.001), heterogeneous echotexture (OR, 7.106; p = 0.001), mass-like lesion type on DCE-MRI (OR, 0.425; p = 0.022), and homogeneous internal enhancement (OR, 0.144; p = 0.001) were all significantly linked to high-TILs. The nomogram based on these characteristics yielded an optimal AUC of 0.884 (95% confidence interval [CI], 0.846-0.921)in the training set and 0.883 (95% CI, 0.825-0.940) in the test set. The calibration curve showed favorable calibration ability.
CONCLUSION: The nomogram includes imaging features from both US and MRI, which are crucial for predicting high levels of TILs in TN and HER2-positive breast cancers.
ADVANCES IN KNOWLEDGE: Pretreatment US and MRI features have the potential to noninvasively predict TILs levels in TN and HER2-positive breast cancer. These findings may aid in treatment decision-making and improve prognostic assessment.Prediction of Tumor-infiltrating Lymphocytes in Triple-negative and HER2-positive Breast Cancer Using Multi-modality Ultrasound and MRI: A Single-institution Retrospective Study.

Keywords:  magnetic resonance imaging; tumour infiltrating lymphocytes; ultrasound

DOI:  https://doi.org/10.1093/bjr/tqaf146
Transfusion. 2025 Jun 30.

Evaluation of a microfluidic chip-based cell sorter in clinical manufacturing processes to deplete or isolate CD4 regulatory T cells.

Ruud Hulspas, M Felicia Ciuculescu, Carolina Sasso, Baochun Zhang, José A Cancelas, Jerome Ritz.

   BACKGROUND: Clinical scale manufacturing for cell therapies requires reliable methods to purify specific cell types. Few microfluidic chip-based cell sorters have been integrated into manufacturing processes of therapeutic cells. Reports have highlighted the need to assess current requirements and explore areas for improvement.
STUDY DESIGN AND METHODS: We evaluated Highway1, a new microfluidic chip-based cell sorter in the context of good manufacturing practice (GMP)-compliant manufacturing processes involving purification of CD4 T cell subsets. Tests explored throughput and processing time limits, as required in GMP-compliant purification of regulatory T cells (Tregs) and of CD4 T cells free of CD4 Tregs. Findings were used to establish conditions with the best balance between processing time and yield.
RESULTS: Best average recovery (60%) was obtained when processed at 1-1.5 million cells/mL, purifying a target population of 33%. Weighing recovery against processing time, a sample concentration of 2.0 million cells/mL offers the optimum condition for sorting CD4 T cells free of CD4 Tregs from healthy blood. Similar tests also show that this device allows for shorter overall processing times to purify CD4 Tregs than previously reported for other microfluidic chip-based sorters, with the additional benefit of an essentially user intervention-free operation.
DISCUSSION: The Highway1 allows for reliable selection of a highly pure subpopulation of CD4 T cells in a GMP-compliant, cell therapy manufacturing setting. As with conventional sorters, the purification process for Tregs still needs to be preceded by a pre-enrichment process to keep the total processing time within an acceptable range for clinical-grade cell manufacturing.

Keywords:  blood center operations; cellular therapy; transfusion service operations

DOI:  https://doi.org/10.1111/trf.18324
PeerJ. 2025 ;13 e19550

High matrix metalloproteinase-2 expression predicts poor prognosis of colon adenocarcinoma and is associated with PD-L1 expression and lymphocyte infiltration.

Yiyi Xiao, Guangming Li, Yongjie Xie, Bo Shao, Jingpeng Hao, Yanglin Zhu, Dejun Kong, Yafei Qin, Hong Qin, Shaohua Ren, Hongda Wang, Chenglu Sun, Hao Wang.

   Background: Colon adenocarcinoma (COAD) is a prevalent and aggressive malignancy with limited treatment options, particularly for advanced stages. While programmed death-ligand 1 (PD-L1) inhibition, has emerged as an appealing therapeutic approach for COAD, its effectiveness as a monotherapy is hindered by high tumor heterogeneity. Identifying novel therapeutic targets to boost the efficacy of PD-L1-based immunotherapy in COAD is crucial to improving clinical outcomes. Matrix metalloproteinase-2 (MMP-2), traditionally known for its role in tumor invasion, metastasis, and angiogenesis, has not been thoroughly investigated in the relationship to immunotherapy for COAD. This work aims to investigate the potential involvement of MMP-2 in the immune microenvironment of COAD and explore its possible role as a target to enhance the therapeutic efficacy of anti-PD-L1-based immunotherapy.
Methods: This study employed a comprehensive bioinformatics analysis of publicly available datasets to investigate the correlation between MMP-2 expression and PD-L1 levels in COAD. Additionally, we evaluated the impact of MMP-2 expression on patient survival and prognosis. To validate these findings, in vitro experiments were conducted to assess the effect of MMP-2 inhibition on PD-L1 expression in colon cancer cell lines. We also analyzed the association between MMP-2 expression and tumor-infiltrating lymphocytes (TILs) to elucidate the immunological landscape of COAD.
Results: Our bioinformatic analysis revealed a novel positive correlation between MMP-2 expression and PD-L1 level in COAD, indicating that higher MMP-2 level is associated with increased PD-L1 expression. Furthermore, in COAD patients, elevated MMP-2 expression was linked to poor overall survival and prognosis. In vitro experiments demonstrated that inhibiting MMP-2 significantly reduced PD-L1 expression in SW480 cells, suggesting that MMP-2 plays a regulatory function in immune evasion. In addition, a novel negative relationship between MMP-2 expression and the presence of TILs was identified, underscoring MMP-2's potential role in modifying the COAD immunological landscape.
Conclusion: This work shows for the first time that MMP-2 not only contributes to tumor progression but also plays a critical role in the immunosuppressive microenvironment of COAD. The demonstrated association between MMP-2 and PD-L1 expression, along with its effect on TILs, indicates that MMP-2 is a promising alternative target for improving the efficacy of anti-PD-L1 immunotherapy. Targeting MMP-2 may offer a novel avenue for overcoming resistance to conventional immunotherapies, potentially improving treatment outcomes in COAD patients.

Keywords:  Colon adenocarcinoma; Immunotherapy; Lymphocyte infiltration; Matrix metalloproteinase-2; PD-L1

DOI:  https://doi.org/10.7717/peerj.19550
Acta Derm Venereol. 2025 Jul 01. 105 adv42882

Inhibitory Immune Checkpoints beyond Programmed Cell Death Ligand 1 in Merkel Cell Carcinoma: Abundant Expression of TIGIT Independent of the Presence of Merkel Cell Polyoma Virus.

Ferdinand Toberer, Julia K Winkler, Leroy Atienza Fernandez, Lea Adams, Alexander Brobeil, Marcell Tóth, Alexander H Enk, Jürgen C Becker, Anke Lonsdorf.

Merkel cell carcinoma is a rare, aggressive skin cancer in which Merkel cell polyoma virus (MCPyV) is frequently pathogenically involved. After failure of anti-programmed cell death protein 1/programmed cell death ligand 1 immunotherapy, therapeutic options for advanced disease are limited. The contribution of the coinhibitory checkpoint molecule T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), a regulator of exhausted CD8+ T cells, to the immunosuppressive Merkel cell carcinoma microenvironment is understudied. This study evaluated the immunohistochemical expression of tumour (Tumor Proportion Score, TPS) and infiltrating immune cells (Immune Cell Score, ICS) for programmed cell death ligand 1, TIGIT, its high-affinity receptor CD155, and CD8 in 21 primary Merkel cell carcinoma and 6 metastases. Unlike CD155, TIGIT was abundantly expressed by tumour and immune cells and independent of the MCPyV status, determined by RT-PCR. Programmed cell death ligand 1+ immune cells were significantly increased in TIGIT TPS-positive and MCPyV-positive primary MCC along with significant intercorrelations of programmed cell death ligand 1 and TIGIT immune cell expression and CD8+ infiltrates. Programmed cell death ligand 1 IC-positivity correlated with superior disease-specific survival. The data indicate that TIGIT may contribute to local immune dysfunction in Merkel cell carcinoma, beyond programmed cell death ligand 1 and independent of MCPyV, and provide a rationale to further explore TIGIT as a potential target for Merkel cell carcinoma immunotherapy.

DOI: https://doi.org/10.2340/actadv.v105.42882
Nat Commun. 2025 Jul 01. 16(1): 5660

Radiation therapy results in preferential tumor antigen-specific lymphodepletion in head and neck cancer.

Joseph Zenga, Musaddiq J Awan, Anne Frei, Jamie Foeckler, Rachel Kuehn, Julia Kasprzak, Becky Massey, Jennifer Bruening, Kenneth Akakpo, Monica Shukla, Stuart J Wong, Angela J Mathison, Jaime Wendt Andrae, Bryan Hunt, Andrii Puzyrenko, Victor X Jin, Abdullah A Memon, Oscar Villarreal Espinosa, Fanghong Chen, Md Shaheduzzaman, Tyce Kearl, Peiman Hematti, Heather A Himburg.

Human Papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) remains a challenging malignancy, with radiotherapy, alone or combined with immune checkpoint inhibitors, often failing to achieve durable disease control. Here, by conducting longitudinal multi-omic analyses of pre- and post-radiation biopsies from patients receiving a pre-operative hypofractionated radiation regimen, we uncover that radiation rapidly depletes a subpopulation of tumor-infiltrating lymphocytes (TIL), characterized by a proliferative, cytotoxic, and tissue-resident gene signature (TProlif_Tox). We provide multi-dimensional evidence for tumor antigen-specificity of TProlif_Tox clonotypes and show that post-radiation tumors are instead repopulated by regulatory and non-specific clones. Finally, TIL depletion correlates with radiorecurrent disease after conventional radiation, emphasizing the potential impact of radiation-induced TIL loss regardless of fractionation. Thus, this study provides key insights into radiotherapy-induced alterations in the immune microenvironment that drive immunologic radioresistance and proposes restoring tumor antigen-specific T cell clonotypes as a strategy to improve radioimmunotherapy responses in HNSCC.

DOI: https://doi.org/10.1038/s41467-025-60827-w
Cell Stem Cell. 2025 Jul 03. pii: S1934-5909(25)00230-9. [Epub ahead of print]32(7): 1031-1033

The future belongs to those who believe in multiplex CAR T engineering.

Laura Volta, Chiara F Magnani.

Toxicity and immune evasion have hindered the success of CAR T cells in HER2-positive solid tumors. In this issue of Cell Stem Cell, Hosking et al. present an iPSC-derived CAR T cell product engineered for tumor-selective targeting, resistance to the immunosuppressive tumor microenvironment, enhanced persistence and trafficking, and mitigation of antigen escape.

DOI: https://doi.org/10.1016/j.stem.2025.06.008
Nat Commun. 2025 Jul 01. 16(1): 5588

Different tumour-resident memory T-cell subsets regulate responses to anti-PD-1 and anti-CTLA-4 cancer immunotherapies.

Isabelle Damei, Aziza Caidi, Edouard Auclin, Julien Adam, Sébastien Mella, Milena Hasan, Eric Tartour, Caroline Robert, Stéphanie Corgnac, Fathia Mami-Chouaib.

The involvement of tumour-resident memory T (TRM) cells in responses to immune checkpoint inhibitors remains unclear. Here, we show that while CD103+CD8 TRM cells are involved in response to PD-1 blockade, CD49a+CD4 TRM cells are required for the response to anti-CTLA-4. Using preclinical mouse models, we demonstrate that the benefits of anti-PD-1 treatment are compromised in animals challenged with anti-CD8 and anti-CD103 blocking antibodies. By contrast, the benefits of anti-CTLA-4 are decreased by anti-CD4 and anti-CD49a neutralizing antibodies. Single-cell RNA sequencing on tumour-infiltrating T-lymphocytes (TIL) reveals a CD49a+CD4 TRM signature, enriched in Ctla-4 transcripts, exacerbated upon anti-CTLA-4. CTLA-4 blockade expands CD49a+CD4 TRM cells and increases tumour-specific CD4-TIL-mediated cytotoxicity. A CD49a+CD4 TRM signature enriched in CTLA-4 and cytotoxicity-linked transcripts is also identified in human TILs. Multiplex immunohistochemistry in a cohort of anti-CTLA-4-plus-anti-PD-1-treated melanomas reveals an increase in CD49a+CD4 T-cell density in pre-treatment tumours, which correlates with higher rates of patient progression-free survival. Thus, CD49a+CD4 TRM cells may correspond to a predictive biomarker of response to combined immunotherapy.

DOI: https://doi.org/10.1038/s41467-025-60657-w
J Natl Cancer Inst. 2025 Jul 02. pii: djaf162. [Epub ahead of print]

Stromal tumor infiltrating lymphocytes and TNBC-DX provide complementary prognostic information in triple-negative breast cancer.

Shane R Stecklein, Miguel Martín, Guillermo Villacampa, María Del Monte-Millan, Rachel Yoder, Harsh Pathak, Sandra Cobo, Fara Brasó-Maristany, Enrique L Álvarez, Isabel Echavarría, Coralia Bueno-Muiño, Yolanda Jerez, María Cebollero, Oscar Bueno, José Á García-Saenz, Fernando Moreno, Henry L Gómez, Tatiana Massarrah, Blanca Herrero, Laia Paré, Mercedes Marín-Aguilera, Wesley Buckingham, Sara López-Tarruella, Patricia Villagrasa, Andrew K Godwin, Roberto Salgado, Aleix Prat, Priyanka Sharma.

Patients with triple-negative breast cancer (TNBC) who achieve pathologic complete response (pCR) to neoadjuvant systemic therapy have favorable survival, while those with residual disease have high recurrence risk. Stromal tumor infiltrating lymphocytes (sTILs) and TNBC-DX both predict pCR in TNBC. Whether these two biomarkers provide complementary information has not been tested. We evaluated sTILs and TNBC-DX in TNBC patients treated with docetaxel-carboplatin (TCb) on the MMJ-CAR-2014-01 study (NCT01560663) or TCb plus pembrolizumab (TCb+Pem) on the NeoPACT trial (NCT03639948). sTILs and TNBC-DX independently predicted pCR in patients treated with TCb+Pem. Patients with sTILs ≥ 30% and a TNBC-DX pCR-high genomic score achieved a pCR rate of 91.3% with TCb+Pem. An integrated classification incorporating sTILs and TNBC-DX identified approximately 40% of the NeoPACT cohort with a pCR rate exceeding 85%. The integrated classification was prognostic for event-free survival in patients treated with TCb+Pem. Integrating sTILs and TNBC-DX may facilitate chemoimmunotherapy escalation and de-escalation trials.

DOI: https://doi.org/10.1093/jnci/djaf162
Breast J. 2025 ;2025 2793342

Extratumoral Signs of Malignant Nonspiculate and Noncalcified Masses on Mammography: Are They Associated With Prognostic Factors in Breast Cancer?

Ye Xu, Xinxin Yang, Fei Wang, Dongbo Wu, Jianghong Sun, Hongxue Meng, Xiushi Zhang.

  Aim: To investigate the association between mammographic extratumoral signs, specifically their subclassifications, of nonspiculate and noncalcified masses (NSNCMs) and prognostic factors in breast cancer. Materials and Methods: This retrospective study analyzed imaging and pathological data from 374 patients, categorizing extratumoral signs into structural abnormalities (parenchymal and trabecular) and halo, while also undergoing subclassification. The focus prognostic factors were achieved through screening. Then, univariate and multivariate analyses were performed. Correlation analysis was also employed to determine the relationship between subclassifications and prognostic factors. Results: Lymphovascular invasion (LVI), Ki-67 levels, and stromal tumor-infiltrating lymphocytes (sTIL) levels were identified as the focus prognostic factors. Among tumor signs, only tumor margin was associated with sTIL levels. Extratumoral trabecular signs exhibited a significant correlation with LVI (OR = 2.5, p=0.007) and Ki-67 levels (OR = 1.23, p=0.001). Specifically, the parallel sign showed a positive correlation with LVI (p=0.009, r = 0.134), while the reticular sign displayed a positive correlation with Ki-67 levels (p=0.009, r = 0.134). Extratumoral parenchymal signs were found to be an independent predictor for sTIL levels (OR = 0.64, p < 0.001), with a negative correlation observed between the contraction sign and sTIL levels (p < 0.001, r = -0.185), as well as between the atrophy sign and sTIL levels (p=0.046, r = -0.103). Conclusion: Specific extratumoral structural abnormalities of mammographic malignant NSNCMs showed a significant correlation with prognostic factors in breast cancer, warranting increased attention in research and clinical practice.

Keywords:  breast cancer; malignant breast nonspiculate and noncalcified masses; mammographic extratumoral structural abnormalities; mammography; nonspiculate and noncalcified masses; prognosis

DOI:  https://doi.org/10.1155/tbj/2793342
J Am Geriatr Soc. 2025 Jul 04.

REPLY: The Assessment Approach of Frailty May Influence Its Prognostic Impact Amidst Clinical Trials.

Tu N Nguyen, Jie Yu, Vlado Perkovic, Clare Arnott, Richard I Lindley.



Keywords:  diabetes mellitus; frailty; frailty assessment; sodium‐glucose cotransporter 2 inhibitor

DOI:  https://doi.org/10.1111/jgs.19598
Hepatology. 2025 Jul 01.

Tumor site influences efficacy of MEKi and immunotherapy combinations in pre-clinical model of cholangiocarcinoma.

Jacklyn Hammons, Emilie K Warren, Megen C Wittling, Frances J Bennett, Guillermo O Rangel-Rivera, Alexis Mack, Maggie Phillips, Brian S Robinson, Alyssa M Krasinskas, Natalie Horvat, Ayana T Ruffin, Yuan Liu, Yichun Cao, Nilofer Azad, Mark Yarchoan, Thatcher Heumann, Tibor Keler, Shishir K Maithel, Chrystal M Paulos, Gregory B Lesinski.

   BACKGROUND AIMS: Although chemotherapy and anti-PD-L1 antibodies are the standard of care for cholangiocarcinoma (CCA), resistance is common and limits durable benefits for patients. This hurdle underscores the urgent need to innovate combination approaches that promote durable immunity in patients. Mek inhibitors (MEKi) have shown potential to enhance immunotherapy in CCA models, but early clinical trials combining MEKi with anti-PD-L1 therapy have yielded suboptimal results.
APPROACH RESULTS: We hypothesized that addition of CD27 agonist would salvage MEKi-induced T cell impairment and reduce CCA burden in vivo. We show CD27 agonism potentiates T cell activation in the presence of MEKi in vitro. Further, triple therapy with CD27 agonist, anti-PD-L1, and MEKi elicit efficacy in a subcutaneous CCA model, accompanied by increases in tumor-infiltrating CD8+ T cells with memory phenotypes. Although triple therapy enhanced CD8+ T cell infiltration in mice with orthotopic CCA liver tumors, its impact on overall survival was less pronounced. Further investigation revealed orthotopic CCA tumors harbored more CD11b+Gr-1+ cells when compared to either subcutaneous CCA tumors, or to normal liver. Finally, in mice with orthotopic CCA tumors treated with triple therapy, depletion of Gr-1+ cells triggered severe toxicity, characterized by rapid weight loss and uncontrolled systemic and hepatic inflammation.
CONCLUSIONS: These findings identify myeloid cells as key mediators of both immunotherapy resistance and toxicity in CCA, highlighting the critical importance of tumor site and use of physiologically relevant pre-clinical models when evaluating immunotherapy strategies.

Keywords:  CD27; MEK inhibition; PD-L1; agonist antibody; biliary tract cancer; immune checkpoint blockade; immunotherapy; myeloid cells

DOI:  https://doi.org/10.1097/HEP.0000000000001439
iScience. 2025 Jul 18. 28(7): 112829

Bispecific targeting of 4-1BB and CCR8 boosts antitumor immunity via Ti-Treg depletion and CD8+ activation.

Jiefang Xu, Ran Wang, Shipeng Cheng, Sonam Wangmo, Jichao Yang, Fuquan Jin, Xiao Lu, Liyan Ma, Ying Zhu, Haoting Sun, Lunxiu Qin, Zhiyang Ling, Yaguang Zhang, Xiaoyu Sun, Chunyan Yi, Bing Sun.

  Immune checkpoint therapy has transformed cancer treatment, yet efficacy and safety challenges persist. Selectively inhibiting tumor-infiltrating regulatory T cells (Ti-Tregs) while enhancing CD8+ T cell function are complementary strategies in cancer immunotherapy. Here, we engineered a bispecific antibody, FRP303, targeting 4-1BB and CCR8, which are co-expressed on a highly immunosuppressive subset of Ti-Tregs. In vivo, FRP303 outperformed monoclonal antibodies in CT26 and MC38 colorectal tumors and poorly immunogenic B16F10 melanoma. Treatment with FRP303 reduced Ti-Treg frequency, increased CD8+ T cell infiltration, and elevated antitumor cytokines IFN-γ and TNF-α. Safety assessments showed FRP303 does not disrupt immune homeostasis in peripheral tissues or induce significant hepatotoxicity. Moreover, FRP303 demonstrated strong synergistic effects when combined with a PD-1 antibody. In summary, FRP303 mediated anti-tumor activity through a dual mechanism involving the selective depletion of Ti-Tregs and the enhancement of CD8+ T cell function, offering a promising strategy for cancer immunotherapy.

Keywords:  Biological sciences; Components of the immune system; Immunology

DOI:  https://doi.org/10.1016/j.isci.2025.112829
Nat Commun. 2025 Jul 03. 16(1): 6123

Tumor site-directed A1R expression enhances CAR T cell function and improves efficacy against solid tumors.

Kevin Sek, Amanda X Y Chen, Thomas Cole, Jesse D Armitage, Junming Tong, Kah Min Yap, Isabelle Munoz, Phoebe A Dunbar, Shiyi Wu, Marit J van Elsas, Olivia Hidajat, Christina Scheffler, Lauren Giuffrida, Melissa A Henderson, Deborah Meyran, Fernando Souza-Fonseca-Guimaraes, Dat Nguyen, Yu-Kuan Huang, Maria N de Menezes, Emily B Derrick, Cheok Weng Chan, Kirsten L Todd, Jack D Chan, Jasmine Li, Junyun Lai, Emma V Petley, Sherly Mardiana, Anthony Bosco, Jason Waithman, Ian A Parish, Christina Mølck, Gregory D Stewart, Lev Kats, Imran G House, Phillip K Darcy, Paul A Beavis.

The efficacy of Chimeric Antigen Receptor T cells against solid tumors is limited by immunosuppressive factors in the tumor microenvironment including adenosine, which suppresses Chimeric Antigen Receptor T cells through activation of the A2A receptor. To overcome this, Chimeric Antigen Receptor T cells are engineered to express A1 receptor, a receptor that signals inversely to A2A receptor. Using murine and human Chimeric Antigen Receptor T cells, constitutive A1 receptor overexpression significantly enhances Chimeric Antigen Receptor T cell effector function albeit at the expense of Chimeric Antigen Receptor T cell persistence. Through a CRISPR/Cas9 homology directed repair "knock-in" approach we demonstrate that Chimeric Antigen Receptor T cells engineered to express A1 receptor in a tumor-localized manner, enhances anti-tumor therapeutic efficacy. This is dependent on the transcription factor IRF8 and is transcriptionally unique when compared to A2A receptor deletion. This data provides a novel approach for enhancing Chimeric Antigen Receptor T cell efficacy in solid tumors and provides proof of principle for site-directed expression of factors that promote effector T cell differentiation.

DOI: https://doi.org/10.1038/s41467-025-59021-9
Pathog Immun. 2025 ;10(2): 146-148

Comments on "Early Activation of Lung CD8+ T Cells After Immunization with Live Plasmodium berghei Malaria Sporozites".

Samiha Fatima.

DOI: https://doi.org/10.20411/pai.v10i2.851
Cell Rep Med. 2025 Jun 26. pii: S2666-3791(25)00282-4. [Epub ahead of print] 102209

Cardiolipin-mimic lipid nanoparticles without antibody modification delivered senolytic in vivo CAR-T therapy for inflamm-aging.

Zihan Zhang, Bin Ma, Buyao Li, Zhiwei Li, Min Gao, Hailong Zhao, Rui Peng, Jiang Hu, Yu Wang, Wei You, Xun Gui, Rui Wang, Xiaoqing Hu, Beidi Chen, Yuanjie Zhang, Yanyun Hao, Xiaolin Sun, Peishi Rao, Liang Zhang, Ming Lu, Demin Zhou, Yun Yang, Mi Deng, Lei Miao.

  mRNA-based in vivo chimeric antigen receptor (CAR)-T cell engineering offers advantages over ex vivo therapies, including streamlined manufacturing and transient expression. However, current delivery methods require antibody-modified vehicles with manufacturing challenges. In this study, inspired by cardiolipin, we identify cardiolipin-like di-phosphoramide lipids that improve T cell transfection without targeting ligands, both in vitro and in vivo. The T cell-favored tropism is likely due to the lipid's packing, shape, and rigidity. Encapsulating circular RNA further prolongs mRNA expression in the spleen and T cells. Using PL40 lipid nanoparticles, we deliver mRNA encoding a CAR targeting the senolytic and inflammatory antigen urokinase-type plasminogen activator receptor (uPAR), alleviating uPAR-related liver fibrosis and rheumatoid arthritis (RA). Single-cell sequencing in humans confirms uPAR's relevance to senescence and inflammation in RA. To facilitate clinical translation, we screen and humanize single-chain variable fragments (scFvs) against uPAR, establishing a PL40 mRNA-encoded humanized uPAR CAR with potential for treating aging-inflamed disorders.

Keywords:  T cells; aging-inflamed disorders; chimeric antigen receptor: CAR; circular mRNA; senolytic; uPAR

DOI:  https://doi.org/10.1016/j.xcrm.2025.102209
NPJ Vaccines. 2025 Jul 04. 10(1): 143

Optimized lentiviral backbone induces robust and diverse T cell immunity against neoantigens to counteract tumor heterogeneity.

Benjamin Vesin, Ingrid Fert, Amandine Noirat, Pierre Authié, Sylvain Ciret, Catherine Blanc, Yakov Vitrenko, Pierre Charneau, Laleh Majlessi, François Anna.

Targeting personalized tumor neoantigens is a promising strategy in immuno-oncotherapy, tumor heterogeneity requires that adaptive immunity be effectively induced against a broad spectrum of neoantigens for a significant anti-tumor effect. We developed several non-integrative lentiviral vectors encoding optimized immunogen that induce robust T cell responses against neoepitopes derived from murine colorectal tumors. Incorporating proteasome-targeting sequences and 4-alanine spacers between neoepitopes enhanced responses to both dominant and subdominant neoepitopes. Using longer natural sequences encompassing minimal epitopes further improved immunogenicity. These vectors drove complete regression of MC38 tumors expressing the selected neoepitopes and sustained immune memory to prevent relapse. Additionally, these vectors synergized with anti-programmed cell death protein 1 (PD1) therapy to inhibit wild-type MC38 tumor growth. Variant allele frequency tracking demonstrated T cells eradicated neoantigen-positive cells without affecting negative ones. Our results validate lentiviral vectors for personalized neoepitope therapy and underscore the need for diverse neoantigens in immunotherapy against tumor mosaicism.

DOI: https://doi.org/10.1038/s41541-025-01199-6
Sci Rep. 2025 Jul 02. 15(1): 23495

Prognostic value of the StAN score in elderly small cell lung cancer.

Feride Yılmaz, Serkan Yaşar, Ömer Denizhan Tatar, Hasan Çağrı Yıldırım, Denizcan Güven, Burak Yasin Aktaş, Hakan Taban, Zafer Arık, Mustafa Erman.

  Lung cancer, the leading cause of cancer-related mortality, includes small-cell lung cancer (SCLC), which accounts for 15% of cases. The median age of lung cancer diagnosis is 71, highlighting the need for accessible prognostic tools in elderly patients. The prognostic nutritional index (PNI) has shown promise in predicting survival in various cancers. This study evaluates the performance of a PNI-based novel scoring system in elderly SCLC patients. We analyzed 117 patients aged ≥ 65 diagnosed with SCLC between 2007 and 2023. Data on age, Eastern Cooperative Oncology Group Scale (ECOG) performance status, hemoglobin levels, disease stage, and PNI were collected. The StAN score, incorporating stage (extensive vs. limited), hemoglobin (normal vs. low), and PNI (< median vs. ≥ median), was derived from multivariate analyses. Patients were classified into low- and high-risk categories. Kaplan-Meier and Cox models assessed overall survival (OS) and progression-free survival (PFS). The median age was 71 years, with 89.7% male patients. Median follow-up was 12.4 months. Patients with low PNI had shorter OS (7.6 vs. 18.2 months, p < 0.001) and PFS (5.4 vs. 10.3 months, p < 0.001). High-risk patients, based on the StAN score, had shorter OS (7.8 vs. 18.5 months, HR 2.38, p < 0.001) and PFS (5.4 vs. 10.3 months, HR 2.29, p < 0.001). Harrell's C indices for predicting OS and PFS were 0.72 and 0.73, respectively. In conclusion, the StAN score is a reliable prognostic tool for elderly SCLC patients and may help stratify patients and improve treatment strategies.

Keywords:  Elderly patients; Geriatric oncology; Nutrition; Prognosis; Prognostic model; Small-cell lung cancer; Survival

DOI:  https://doi.org/10.1038/s41598-025-08115-x
Front Oncol. 2025 ;15 1617683

Comprehensive risk score of the E-PASS scoring system serves a prognostic indicator for patients after neoadjuvant therapy and curative esophageal cancer surgery: a multicenter retrospective study.

Nanjing Li, Yixin Liu, Jianfeng Zhou, Xiang Li, Shenglu Lian, Yushang Yang.

   Background: Neoadjuvant chemoradiotherapy (nCRT) and curative surgery have been recommended as the standard treatments for locally advanced esophageal cancer. Nevertheless, the postoperative morbidity and long-term survival outcomes for patients following this consensus treatment plan remain suboptimal. Therefore, preoperative risk assessment is essential to identify high-risk patients and predict adverse postoperative outcomes. This multicenter study aimed to evaluate the Estimation of Physiologic Ability and Surgical Stress (E-PASS) scoring system for predicting the short- and long-term outcomes of esophageal cancer patients treated with nCRT and curative esophagectomy.
Methods: Patients with esophageal cancer who underwent curative resection between 2010 and 2022 were retrospectively enrolled in this study. The cohort was divided into the low and high comprehensive risk score (CRS) groups. The CRS cutoff value was determined using the Youden index applied to overall survival (OS) curves. Prognostic value was assessed through Cox regression and Kaplan-Meier analyses.
Results: In total, 814 patients were enrolled, including 556 and 258 patients with low and high CRS, respectively. ROC curve analysis determined that the CRS was a highly specific and sensitive predictive tool for postoperative complication occurrence and severity (AUC=0.889 and 0.838, respectively). When the cutoff value was established using the Youden index applied to overall OS curves, multivariate analysis demonstrated that the CRS was an independent prognostic factor for OS (HR: 1.48; 95% CI 1.14-1.92, P=0.003) and recurrence-free survival (RFS) (HR: 1.44; 95% CI 1.13- 1.82, P=0.002). Furthermore, the Kaplan-Meier survival curves of OS and RFS also demonstrated high CRS group had worse long-term outcomes, irrespective of tumor regression scores and esophageal cancer stage.
Conclusions: The E-PASS scoring system emerges as a visible predictor of short- and long-term outcomes in patients with esophageal cancer undergoing nCRT and curative surgery.

Keywords:  E-PASS; curative resection; esophageal cancer; neoadjuvant; survival & prognosis

DOI:  https://doi.org/10.3389/fonc.2025.1617683