bims-tuinly 2025-10-26 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–10–26
eleven papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Letter to the Editor: Reconsidering the Role of CD8+ Tumor-Infiltrating Lymphocytes in Recurrent High-Grade Gliomas Treated With Cisplatin and Alternating Temozolomide.
Differential effects of immobilized CCL21 and ICAM1 on TILs with distinct expansion properties.
Flagellin co-expression potentiates mRNA vaccine-induced cytotoxic T lymphocyte responses but not anti-tumor immunity.
Association of tumor-infiltrating lymphocyte subtypes with clinical characteristics and prognosis in young women with hormone receptor-positive breast cancer.
Digital Immunophenotyping of Lung Atypical Carcinoids and Large Cell Neuroendocrine Carcinomas Identifies Three Subtypes With Specific Tumor-Immune Microenvironment Features.
Circulating neoantigen- and viral oncoprotein-specific CD8+ T cells share a transcriptional signature.
The feasibility of the radiomics models for tumor-infiltrating lymphocytes level prediction in breast cancer based on dynamic contrast-enhanced MRI.
A pan-immunotherapy signature to predict intratumoral CD8+ T cell expansions.
Single-cell atlas of the esophageal squamous cell carcinoma immune ecosystem to predict immunotherapy response.
Neoantigen identification and TCR-T therapy development for solid tumors: current advances and future perspectives.
Targeted alpha therapy of ovarian cancer with 212Pb-labeled anti-PTK7 antibody: On-site 212Pb production and preclinical insights.

Clin Med Insights Oncol. 2025 ;19 11795549251385073

Letter to the Editor: Reconsidering the Role of CD8+ Tumor-Infiltrating Lymphocytes in Recurrent High-Grade Gliomas Treated With Cisplatin and Alternating Temozolomide.

Schawanya Kaewpitoon Rattanapitoon, Natnapa Heebkaew Padchasuwan, Nav La, Nathkapach Kaewpitoon Rattanapitoon.

DOI: https://doi.org/10.1177/11795549251385073
Front Immunol. 2025 ;16 1625118

Differential effects of immobilized CCL21 and ICAM1 on TILs with distinct expansion properties.

Sofi Yado, Rawan Zoabi, Karin Brezinger-Dayan, Shira Albeck, Tamar Unger, Moran Meiron, Galit Eisenberg, Alessio D Nahmad, Aya Tzur Gilat, Michal J Besser, Benjamin Geiger.

  Adoptive T cell therapy (ACT), particularly tumor-infiltrating lymphocyte (TIL)-based therapy holds great promise for cancer treatment, yet it still faces major challenges such as patient-to-patient variability in expansion rates and cytotoxic potency. Recent studies suggest that a "synthetic immune niche" (SIN), composed of immobilized CCL21 and ICAM-1, can enhance both the expansion and cytotoxicity of murine and patient-derived T cells. To explore the mechanisms underlying the variability of expansion and cytotoxic potency, we conducted morphological and molecular phenotyping of TIL specimens from different donors immediately following the pre-Rapid Expansion Protocol (pre-REP) stage, enabling us to predict their expansion potential. We further developed novel SIN-based strategies that differentially reinforce the efficacy of both low- and high-expanding TILs. Our experiments revealed two distinct TIL groups with either low- or high-proliferation properties, identified across cultures derived from different patients. We further demonstrate that a 14-day REP with feeder cells and SIN facilitates the proliferation of the low-expanding cells, while the expansion of high-expanding TILs benefits from a sequential expansion protocol, consisting of 7 days with feeder cells only, followed by 7 days with SIN treatment. At the end of the REP both TIL populations display high levels of granzyme B and perforin and reduced levels of exhaustion markers. Importantly, functional cytotoxicity assays using autologous tumor targets demonstrated that SIN stimulation improved the tumor-killing capacity of low-expanding TILs, while preserving the potent cytotoxicity of the high-expanding TILs. These data indicate that the refined CCL21+ICAM1 SIN treatment improves expansion rates and activation profiles of both TIL populations, thereby enabling a powerful, personalized SIN-enhanced protocol for TIL-based immunotherapy.

Keywords:  CCL21 + ICAM1 synthetic immune niche (SIN); T cells; T-cell morphology; TIL expansion; adoptive T cell therapy (ACT); pre-REP TILs; rapid expansion protocol (REP); tumor-infiltrating lymphocytes (TILs)

DOI:  https://doi.org/10.3389/fimmu.2025.1625118
Sci Rep. 2025 Oct 24. 15(1): 37280

Flagellin co-expression potentiates mRNA vaccine-induced cytotoxic T lymphocyte responses but not anti-tumor immunity.

Yibo Li, Xinliang Kang, Yuna Song, Labone Akter, Elise VanLuinen, Jayachandra Reddy Nakkala, Xinyuan Chen.

  Personalized neoantigen mRNA vaccine showed high potency to treat advanced melanoma and pancreatic cancer in recent clinical trials. Strategies to further increase its therapeutic efficacy are highly demanded. This study explored flagellin to increase model antigen ovalbumin (OVA) mRNA-induced cytotoxic T lymphocyte (CTL) responses and anti-tumor immunity in OVA-expressing B16F10 melanoma models. To minimize the potential negative impact of flagellin-induced signaling pathways on OVA mRNA translation, flagellin mRNA was used in our studies. We found flagellin-OVA mRNA (co-expression) but not flagellin mRNA/OVA mRNA (separate expression) significantly increased granzyme B, perforin, and interferon γ-secreting CD8+ and CD4+ T cell levels in spleen of tumor-bearing mice. Flagellin co-expression but not separate expression also significantly increased perforin+ CD8+ tumor-infiltrating lymphocytes (TILs) and perforin+ and granzyme B+ CD4+ TILs. To our surprise, flagellin co-expression and separate expression significantly reduced CD8+ TILs as compared to OVA mRNA alone. The ratio of CD8+ to CD4+ TILs was significantly increased by OVA mRNA vaccination alone or with flagellin co-expression but not with flagellin separate expression. The ratio of CD8+ to CD4+ TILs was significantly higher in flagellin co-expression than separate expression group. Collectively, flagellin co-expression more significantly reduced tumor growth rate than flagellin separate expression but only slightly reduced tumor growth rate as compared to OVA mRNA alone. In summary, these results support flagellin co-expression to enhance mRNA vaccine-induced CTL responses, yet strategies are demanded to promote tumor infiltration of elicited peripheral CTLs.

Keywords:  Adjuvant; Flagellin; Immunotherapy; Tumor vaccine; mRNA vaccine

DOI:  https://doi.org/10.1038/s41598-025-21238-5
Clin Cancer Res. 2025 Oct 21.

Association of tumor-infiltrating lymphocyte subtypes with clinical characteristics and prognosis in young women with hormone receptor-positive breast cancer.

Megan E Tesch, Yue Zheng, Yaileen D Guzman-Arocho, Laura C Collins, Yu Jing J Heng, Nabihah Tayob, Shoshana M Rosenberg, Kathryn J Ruddy, Rulla M Tamimi, Lidia Schapira, Jeffrey Peppercorn, Virginia Borges, Steven E Come, Craig Snow, Eric Winer, Elizabeth A Mittendorf, Ann H Partridge.

BACKGROUND: The role of tumor-infiltrating lymphocytes (TILs) remains unclear in hormone receptor (HR)-positive/HER2-negative breast cancer, particularly in young patients, whose immune microenvironment could be altered by age-related host and tumor differences.
PATIENTS AND METHODS: Patients with stage I-III HR-positive/HER2-negative tumors were identified from a prospective cohort study of breast cancer patients diagnosed at age ≤ 40 years. Multiplexed immunofluorescence and semiautomated quantitative software measured cytotoxic T, non-CD8 T, T regulatory, exhausted T, and PDL1+ cells in stroma and tumor. Univariate analyses assessed differences in clinicopathologic characteristics by high versus low immune infiltration, divided based on median. TIL subtypes were evaluated as a continuous variable per 10% increase in Cox regression analyses for invasive breast cancer-free survival (iBCFS), distant disease-free survival (DDFS), and overall survival (OS), adjusted for clinicopathologic parameters.
RESULTS: Among 390 patients, high immune infiltration was associated with increasing age, Black race, grade 3 tumors, and metaplastic or micropapillary histological subtypes. Over a median follow-up of 8 years, higher stromal and intratumoral non-CD8 T cell infiltration, T regulatory cell infiltration, and PDL1 expression was associated with improved iBCFS. Higher intratumoral non-CD8 T cell infiltration, T regulatory cell infiltration, and PDL1 expression was associated with improved DDFS; higher stromal PDL1 expression was also associated with improved DDFS. Higher intratumoral cytotoxic T cell infiltration and PDL1 expression was associated with improved OS.
CONCLUSIONS: Characterization of immune subpopulations could help refine the prognostic value of TILs in young patients with HR-positive breast cancer, who may benefit from risk stratification for treatment individualization.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-0948
Endocr Pathol. 2025 Oct 24. 36(1): 39

Digital Immunophenotyping of Lung Atypical Carcinoids and Large Cell Neuroendocrine Carcinomas Identifies Three Subtypes With Specific Tumor-Immune Microenvironment Features.

Giovanni Centonze, Patrick Maisonneuve, Émilie Mathian, Federica Grillo, Giovanna Sabella, Vincenzo Lagano, Alessandro Mangogna, Sara Pusceddu, Paola Bossi, Paola Spaggiari, Alessandro Del Gobbo, Stefano Ferrero, Luigi Rolli, Ugo Pastorino, Luisa Bercich, Andrea Tironi, Mauro Roberto Benvenuti, Maria Sole Gallazzi, Rosalia Romano, Alfredo Berruti, Luca Roz, Carlo Capella, Matthieu Foll, Massimo Milione.

  Atypical carcinoids (ACs) and large cell neuroendocrine carcinomas (LCNECs) are defined by the WHO as intermediate- and high-grade lung neuroendocrine neoplasms, respectively, based on morphological criteria; however, treatment strategies remain debated. Given the emerging role of the tumor microenvironment (TME) and tumor-infiltrating lymphocytes (TILs) in cancer prognosis and therapy response, this study aimed to characterize the immune landscape of ACs and LCNECs comprehensively. Immunohistochemistry for T-cell markers (CD3, CD8), immune checkpoints (PD-1, PD-L1), HLA molecules (HLA-DR, HLA-I), and fibroblasts (α-SMA) was performed on a re-evaluated cohort of 56 ACs and 104 LCNECs. Digital image analysis quantified intra-tumor (iTILs) and stromal (sTILs) CD3 and CD8 TILs in the whole slide and in specific tumor regions (invasive margin [IM] and central tumor [CT]). LCNECs exhibited significantly higher stromal T-cell infiltration, immune checkpoint expression, and HLA compared to ACs (p < 0.001), while α-SMA was more prominent in ACs. No ACs showed PD-L1 tumor expression. Digital quantification confirmed greater iTILs and sTILs in LCNECs across all regions, with moderate concordance to manual counts. Interestingly, TIL parameters were higher at the IM than in the CT (p < 0.001). Using Boruta feature selection algorithm, Principal Component Analysis and Hierarchical Clustering, three patient clusters were identified: Cluster 1 (mainly ACs, low TILs, favorable prognosis), Cluster 2 (mixed histology, intermediate TILs, moderate prognosis), and Cluster 3 (mostly LCNECs, high TILs, poor prognosis), with distinct TME marker profiles. PD-L1 tumor expression was strongly linked to Cluster 3. These findings suggest that ACs and LCNECs may be stratified into three distinct immune clusters, highlighting the heterogeneity of their tumor microenvironment and providing a rationale for further translational studies.

Keywords:  Atypical carcinoid; Digital immunophenotyping; Immune clustering; Large cell neuroendocrine carcinomas; Tumor microenvironment; Tumor-infiltrating lymphocyte

DOI:  https://doi.org/10.1007/s12022-025-09886-9
Cancer Immunol Res. 2025 Oct 23.

Circulating neoantigen- and viral oncoprotein-specific CD8+ T cells share a transcriptional signature.

Saumya Jani, Tomas Bencomo, Carolyn Shasha, Thomas Pulliam, Ana Jojic, Candice D Church, Ted A Gooley, David M Koelle, Evan W Newell, Paul Nghiem.

Tumor-specific CD8+ T cells in blood appear to be important for and predictive of response to anti-PD-1 therapies. However, as most tumor antigens are unique to a given patient, identification of tumor-specific CD8+ T cells is not routinely feasible. Here, we characterized polyomavirus-specific CD8+ T cells from blood of 17 patients with virus-driven Merkel cell carcinoma (MCC). We identified a 98-gene signature, SPoTT (Signature of Peripheral Tumor-specific CD8+ T cells), that discriminated circulating tumor-specific CD8+ T cells from other T cells in immunotherapy-naïve patients. We observed profound transcriptomic differences among tumor-specific CD8+ T cells from blood versus from tumor. In validation cohorts of MCC, as well as neoantigen-driven cancers, SPoTT was able to identify viral oncoprotein- and neoantigen-specific CD8+ T cells with both sensitivity and specificity above 75%. We also tested a previously described 151-gene signature (NeoTCR_PBL) trained on neoantigen-specific CD8+ T cells and found it was able to recognize MCPyV-specific T cells with sensitivity of 66% and a specificity of 88%. These findings show that circulating tumor-specific CD8+ T cells share fundamental characteristics across diverse tumor antigen types. More broadly, insights into antitumor T cells gained from virus-driven cancers are also likely to be relevant in mutationally-driven cancers.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-0082
BMC Med Imaging. 2025 Oct 21. 25(1): 420

The feasibility of the radiomics models for tumor-infiltrating lymphocytes level prediction in breast cancer based on dynamic contrast-enhanced MRI.

Yuan Peng, Xuege Hu, Yulu Liu, Dingbao Chen, Xiufeng Chen, Yi Wang, Shu Wang.

   BACKGROUND: Determining tumor-infiltrating lymphocyte (TIL) expression in breast cancer prior to treatment initiation is of considerable clinical significance. MRI demonstrates potential as a valuable adjunct to histopathological assessment. This study investigated the feasibility of developing a radiomics-based predictive model incorporating MRI and clinical features to determine TIL levels in breast cancer.
METHODS: This multicenter retrospective cohort study enrolled 501 patients across two institutions. A total of 453 patients were utilized for model development, comprising a training cohort (n = 317) and internal validation cohort (n = 136), while 48 patients from an external center constituted the independent test cohort. Radiomics features were extracted and subsequently selected using ANOVA and LASSO regression. Logistic regression algorithms were employed for model construction. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the discriminative performance between low-level and intermediate-high-level TILs, comparing the radiomics model with the integrated clinical-radiomics model.
RESULTS: The MRI-based radiomics model demonstrated robust performance for TIL level prediction across both training and internal validation cohorts, achieving areas under the curve (AUC) of 0.810 (95% confidence interval [CI]: 0.781-0.874) and 0.756 (95% CI: 0.676-0.837), respectively. The integrated clinical-radiomics model exhibited superior discriminative performance with AUCs of 0.828 (95% CI: 0.762-0.858) and 0.824 (95% CI: 0.755-0.893) for the training and validation cohorts, respectively. In the external independent test cohort, the radiomics model and integrated model achieved AUCs of 0.704 (95% CI: 0.558-0.850) and 0.767 (95% CI: 0.633-0.901), respectively.
CONCLUSIONS: Radiomics features extracted from dynamic contrast-enhanced MRI, when integrated with clinical characteristics, represent a promising non-invasive approach for predicting TIL levels in breast cancer. This methodology may facilitate clinical decision-making through enhanced pretreatment tumor characterization without requiring invasive tissue sampling.

Keywords:  Breast cancer; Magnetic resonance imaging; Radiomics model; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1186/s12880-025-01968-8
Nat Commun. 2025 Oct 20. 16(1): 9175

A pan-immunotherapy signature to predict intratumoral CD8+ T cell expansions.

Munetomo Takahashi, Mikiya Tsunoda, Hiroyasu Aoki, Masaki Kurosu, Haru Ogiwara, Shigeyuki Shichino, David Bending, Shumpei Ishikawa, James E D Thaventhiran, Kouji Matsushima, Satoshi Ueha.

Effective cancer immunotherapy relies on the clonal proliferation and expansion of CD8+ T cells in the tumor. However, our insights into clonal expansions are limited, owing to an inability to track the same clones in tumors over time. Here, we develop a multi-site tumor mouse model system to track hundreds of expanding and contracting CD8+ T cell clones over multiple timepoints in tumors of the same individual. Through coupling of clonal expansion dynamics and single-cell RNA/TCR-seq data, we identify a transcriptomic signature in PD-1+Ly108+ precursor exhausted cells that strongly predicts rates of intratumoral clone expansion. The signature correlates with expansion in mice, both with and without immunotherapies, and in patients undergoing PD-1 blockade therapy. Expression of the signature during treatment corresponds with positive clinical outcomes. Downregulation of the signature precedes clone contraction-a phase in which clones contract but maintain revivable precursor exhausted cells in the tumor. LAG-3 blockade re-activates the expansion signature, re-expanding pre-existing clones, including previously contracted clones. These findings reveal how the study of clonal expansion dynamics provide a powerful 'pan-immunotherapy' signature for monitoring immunotherapies with implications for their future development.

DOI: https://doi.org/10.1038/s41467-025-64107-5
Signal Transduct Target Ther. 2025 Oct 20. 10(1): 348

Single-cell atlas of the esophageal squamous cell carcinoma immune ecosystem to predict immunotherapy response.

Xiankai Chen, Yahui Zhao, Yuhao Wang, Xiliang Wang, Yuhao Liu, Zhihua Liu, Yin Li.

Esophageal squamous cell carcinoma (ESCC) evolves within a highly interactive tumor microenvironment (TME) that shapes therapeutic response. We utilized mass cytometry to analyze over 10 million cells from 25 ESCC tumors, 24 adjacent nontumor tissues, and 23 peripheral blood samples, employing an extensive panel of 42 immune markers. The resulting atlas reveals a compartmentalized landscape with a reproducible paucity of CD4⁺ and CD8⁺ central memory T cells (TCM) in tumor sites. Reintroduction of patient-derived TCMs restored antitumor immunity in coculture assays, demonstrating their cytotoxic capacity in vitro and suggesting their potential relevance for future therapeutic exploration. Myeloid profiling identified PD-L1⁺ tumor-associated macrophages (TAMs) as correlates of clinical benefit; ex vivo PD-L1 blockade reprogrammed TAMs toward proinflammatory states, indicating pharmacological malleability. Notably, CD39⁺ tumor-infiltrating T cells were consistently associated with favorable prognosis and increased responsiveness to PD-1 blockade across cancer types. The functional inhibition of CD39 impaired cytotoxic T-cell activity, underscoring its dual role as a marker of immune dysfunction and a promising therapeutic target. Collectively, our findings provide a comprehensive immune landscape of ESCC, highlighting key immunological deficits and opportunities for targeted interventions. The insights gained underscore the potential of tailoring immunotherapies to the specific immune profiles of the TME, potentially revolutionizing treatment paradigms for ESCC patients. This study sets the stage for a more nuanced understanding and manipulation of the immune elements critical for optimizing cancer immunotherapy.

DOI: https://doi.org/10.1038/s41392-025-02446-x
J Natl Cancer Cent. 2025 Oct;5(5): 429-440

Neoantigen identification and TCR-T therapy development for solid tumors: current advances and future perspectives.

Xinyao Zheng, Yahui Zhao, Zhihua Liu.

  Recently, T cells expressing engineered T cell receptor (TCR-T cells) have become recognized as a promising tumor cell therapy for solid tumors because of their ability to selectively kill tumor cells with less destruction of other cells and their high safety when used as autologous T cells. Several studies and clinical tests have been conducted to demonstrate its potential as a novel therapy. However, previous research has mainly focused on antigens; these common targets for TCR-T are tumor-associated antigens, which exhibit expression not only in tumor cells but also in normal cells, resulting in off-target risk and not considering the heterogeneity of different patients. In contrast, neoantigens offer superior specificity as they are uniquely expressed on tumor cells due to genomic alterations. Given the frequent occurrence and notable role of genetic mutations in tumorigenesis and tumor progression, identification and targeting of neoantigens is a valuable therapeutic direction. This perspective delves into various antigen classifications, including their characteristics and advantages, as well as strategies for identifying and validating neoantigens that have emerged from numerous research studies. These insights are crucial for guiding the search for new neoantigens. We also review significant and representative studies involving TCR-T and other immunotherapies that target neoantigens to assess the therapeutic effectiveness of TCR-T therapy. Moreover, we discuss the challenges and complexities inherent in TCR-T therapy and propose potential solutions for these issues. In this perspective, we aim to provide fresh perceptions and strategies for cancer treatment by highlighting the potential of TCR-T and exploring its challenges and future directions. It also seeks to propel the development of precision medicine and personalized therapy, offering hope for more effective and targeted cancer treatments in the future.

Keywords:  CAR-T; Immunotherapy; Neoantigen; TCR-T

DOI:  https://doi.org/10.1016/j.jncc.2025.07.001
Nucl Med Biol. 2025 Oct 10. pii: S0969-8051(25)00579-7. [Epub ahead of print]150-151 109570

Targeted alpha therapy of ovarian cancer with 212Pb-labeled anti-PTK7 antibody: On-site 212Pb production and preclinical insights.

Yani Berckmans, Roxanne Wouters, Zeljka Raskovic-Lovre, Sara Van Mechelen, Kim Lindland, Tina Bønsdorff, An Coosemans, Frederik Cleeren.

   BACKGROUND: Targeted alpha therapy (TAT) is recognized as a promising approach for eradicating tumor micro-metastases, owing to its high linear energy transfer. These micro-metastases are often associated with elevated recurrence across various cancer types, including high-grade serous ovarian cancer (HGSOC). In HGSOC, overexpression of the protein tyrosine kinase 7 (PTK7) has been correlated to a worse prognosis. Consequently, the objective of this study was to preclinically evaluate the 212Pb-radiolabeled PTK7-targeting chOI-1 antibody ([212Pb]Pb-TCMC-chOI-1) for intraperitoneal (IP) TAT in HGSOC.
METHODS: Binding and internalization of the chOI-1 antibody was evaluated using respectively flow cytometry and live cell imaging in A2780 human ovarian cancer cells. A two-step column generator was used for on-site 212Pb production. Following quality control, [212Pb]Pb-TCMC-chOI-1 was evaluated in vitro for cytotoxicity and in vivo for biodistribution and efficacy in IP A2780 tumor-bearing mice, after IP administration.
RESULTS: Anti-PTK7 chOI-1 antibodies demonstrated specific binding and internalization in A2780 cells. Lead-212 production was successfully achieved using the 224Ra-based two-step column generator. Subsequent radiolabeling resulted in a radiochemical yield of >85 %. In vitro, [212Pb]Pb-TCMC-chOI-1 enhanced cytotoxicity in A2780 cells. In vivo, tumor uptake was observed 24 h after IP administration (17.98 ± 7.85 %ID/g). Additionally, [212Pb]Pb-TCMC-chOI-1 significantly improved the median survival of A2780 tumor-bearing mice (42 days) compared to vehicle-treated controls (25.5 days).
CONCLUSIONS: [212Pb]Pb-TCMC-chOI-1 was efficiently produced and demonstrated PTK7 specificity and potent cytotoxic efficacy, confirmed through both in vitro and in vivo studies. This highlights the therapeutic potential of [212Pb]Pb-TCMC-chOI-1 for the treatment of metastatic HGSOC following IP administration.

Keywords:  Antibody; Lead-212; Ovarian cancer; PTK7; Targeted alpha therapy

DOI:  https://doi.org/10.1016/j.nucmedbio.2025.109570