bims-tuinly 2025-11-16 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–11–16
thirty papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

The promise of TIL therapy for glioblastoma.
Artificial Intelligence in Histopathological Analysis for Predicting Immunotherapy Response in Cutaneous Melanoma.
Mechanisms of resistance to adoptive cell therapy with tumor-infiltrating lymphocytes.
Dynamic tumor-infiltrating lymphocytes predicts survival in HR+/HER2- early breast cancer: a pre-to-post neoadjuvant chemotherapy study.
Targeted Hyaluronan Degradation Enhanced Tumor Growth Inhibition in Gastrointestinal Cancer Models.
Clinical signiﬁcance of CD155 expression and correlation with immune cell infiltration in triple-negative breast cancer.
An early relapse prediction model based on pathological features following neoadjuvant immunotherapy for hepatocellular carcinoma.
Response to correspondence on 'Deep learning-based quantification of tumor-infiltrating lymphocytes as a prognostic indicator in nasopharyngeal carcinoma: multicohort findings'.
Editorial: Cellular immunotherapy: transforming cancer treatment.
Performance of Machine Learning Models Based on Medical Imaging in Predicting the expression of PD-L1 and CD8+TILs in Thoracic cancer: A Systematic Review and Meta-Analysis.
Targeting asparagine potentiates anti-PD-L1 immunotherapy in gastric cancer by enhancing CD8+ T cell anti-tumor response.
B lymphocytes and tertiary lymphoid structures have a prognostic impact on penile squamous cell carcinoma.
PRDM15 inhibits responses of Tissue-Resident memory T cells by activating PVR/TIGIT axis to mediate gastric cancer immunosuppression.
Harnessing Arginase-2-specific CD8+ T cells to target immunosuppressive Cutaneous T cell Lymphoma.
Novel growth pattern-specific digital marker of TILs improves stratification of lung adenocarcinoma patients.
Method for generation and ex vivo expansion of genetically edited mouse Tregs.
Reprogramming the tumor microenvironment to boost adoptive T cell therapy.
Targeting the HMGB1-IL32 pathway to alleviate T cell exhaustion in epithelial ovarian cancer.
SPP1+ TAM: CD8+ T Cell Crosstalk Associates with Blocking Radiotherapy Efficacy in Lung Cancer.
Synergistic changes in bystander CD8 and conventional CD4 T cells during neoadjuvant chemoimmunotherapy for non-small cell lung cancer reveal treatment response.
Composition and functional state of T and NK cells in the extramedullary myeloma tumor microenvironment.
Response to Immune Checkpoint Blockade is Enhanced in the Presence of Hematopoietic TET2 Inactivation.
Diagnostic accuracy of interferon-gamma release assay and mucosal-associated invariant T cells in spinal tuberculosis.
TAMs-mediated resistance to oncolytic virus M1 in solid tumors.
Mathematical modelling of tumor-immune interactions in breast cancer.
FOXO1-driven metabolic reprogramming of hematomal CD8+ T cells drives the expansion of perihematomal edema following intracerebral hemorrhage.
CXCR3 enhanced murine chimeric antigen receptor T cells in the treatment of solid tumors.
Fermenting T cell stemness for cancer immunity.
Multi-parametric profiling of IL-7-augmented GD2.CART products in a phase 1 clinical trial.
Multi-compartment immune cell profiling highlights the prognostic relevance of CD127+ CD8+ T cells for patients with high-grade serous ovarian cancer.

Trends Cancer. 2025 Nov 13. pii: S2405-8033(25)00254-7. [Epub ahead of print]

The promise of TIL therapy for glioblastoma.

Emma L Pristo, Kelly M Hotchkiss, Anna M Corcoran, Pamela Noldner, Hideho Okada, John W Hickey, Jose Conejo-Garcia, Beth Shaz, Mustafa Khasraw.

  Tumor-infiltrating lymphocyte (TIL) therapy has demonstrated efficacy in refractory melanoma and durable responses in lung cancer. Glioblastoma presents distinct challenges for immunotherapy, including profound tumor heterogeneity, low T cell infiltration, and an immunosuppressive microenvironment, but these same features highlight the unique rationale for TILs. Unlike monoclonal engineered approaches, TILs retain natural polyclonality, enabling recognition of a diverse set of tumor-associated antigens and potential adaptation to the evolving antigenic landscape. Preliminary studies have already shown that tumor-reactive TILs can be successfully isolated and expanded from glioblastoma specimens, providing feasibility for clinical translation. This review discusses the current landscape of TIL therapy in glioblastoma, highlights recent advancements, and discusses future directions and clinical translation to position TIL therapy as a promising and adaptable cellular immunotherapy for one of the most treatment-resistant human cancers.

Keywords:  T cell therapy; glioblastoma; immunotherapy; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.trecan.2025.10.003
Int J Mol Sci. 2025 Nov 04. pii: 10729. [Epub ahead of print]26(21):

Artificial Intelligence in Histopathological Analysis for Predicting Immunotherapy Response in Cutaneous Melanoma.

Seungah Yoo, Ji Hyun Lee.

  Artificial intelligence (AI) has emerged as a transformative tool in histopathology, offering new opportunities to enhance prognostic accuracy and guide immunotherapy in cutaneous melanoma. The prognostic significance of tumor-infiltrating lymphocytes (TILs) is well established, yet their manual assessment remains subjective, labor-intensive, and often confined to selected tissue regions. Recent AI-based approaches enabled automated and reproducible quantification of TIL density and spatial immune profiling across whole-slide images, providing a more comprehensive view of the tumor immune microenvironment. In melanoma, these methods have demonstrated the potential to predict response to immune checkpoint blockade, with spatially resolved TIL profiling emerging as a particularly powerful prognostic and predictive biomarker. This review summarizes recent advances in AI-driven histopathologic analysis of cutaneous melanoma, focusing on automated TIL quantification and spatial immune profiling, and highlights how these innovations refine prognostic evaluation and improve the prediction of immunotherapy outcomes.

Keywords:  artificial intelligence; immunotherapy; melanoma; pathology; tertiary lymphoid structures; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/ijms262110729
Expert Rev Clin Immunol. 2025 Nov 10.

Mechanisms of resistance to adoptive cell therapy with tumor-infiltrating lymphocytes.

David König, Heinz Läubli.

   INTRODUCTION: Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) has become standard treatment for patients with melanoma after the publication of a phase III trial showing an improvement of progression-free survival of metastatic melanoma patients treated with TIL-ACT compared to patients treated with the immune checkpoint inhibitor ipilimumab. Recent clinical trials also tested TIL-ACT in patients with other immunogenic cancers including non-small cell lung cancer or cervical carcinomas.
AREAS COVERED: Some factors were associated with long-term response to TIL-ACT including the number of cells applied to the patient or ratios of CD8+ versus CD4+ T cells. Here, we summarize known factors that are associated with response or resistance to TIL-ACT. We also give an outlook, which factors could be improved to overcome resistance and to enhance long-term outcome of patients.
EXPERT OPINION: TIL-ACT shows promise beyond niche use, but its success depends on overcoming resistance driven by patient, tumor, and product factors. Advancing its efficacy will require refined patient selection, TIL optimization, and mechanistic insights to inform new, improved treatment approaches.

Keywords:  Adoptive cell therapy; Melanoma; NSCLC; Resistance; Response; Tumor-infiltrating lymphocytes; resistance mechanisms

DOI:  https://doi.org/10.1080/1744666X.2025.2588776
Breast Cancer Res. 2025 Nov 14. 27(1): 205

Dynamic tumor-infiltrating lymphocytes predicts survival in HR+/HER2- early breast cancer: a pre-to-post neoadjuvant chemotherapy study.

Yibin Qiu, Renren Zhang, Shunyi Liu, Long Wu, Yali Wang, Weifeng Cai, Peng He, Qindong Cai, Yuxiang Lin, Wenhui Guo, Chuan Wang, Jie Zhang.

   INTRODUCTION: The prognostic implications of tumor-infiltrating lymphocytes (TILs) and their temporal changes (ΔTILs) during neoadjuvant chemotherapy (NAC) in hormone receptor-positive/ HER2-negative early breast cancer (HR+/HER2- eBC) remains clinically ambiguous. Our study investigates the association between TILs levels, longitudinal TILs evolution, and survival outcomes in a NAC-treated HR+/HER2- eBC cohort.
METHODS: In this retrospective cohort analysis of 576 HR+/HER2- eBC patients (April 2011-December 2021), TILs were categorized as low (< 10%) or high (≥ 10%) using predefined thresholds. Multivariable Cox proportional hazards models evaluated invasive disease-free survival (iDFS) and overall survival (OS). ΔTILs patterns were analyzed in residual tumors.
RESULTS: The cohort (median follow-up 68.1 months) comprised 393 TILs-low (68.2%) and 183 TILs-high (31.8%) tumors. Compared to TILs-low tumors, TILs-high tumors were associated with a higher Ki-67 index (≥ 20%) (P = 0.022), even though they were more frequently of smaller baseline size (< 3 cm) (P = 0.022). Elevated pre-NAC TILs independently predicted inferior iDFS (HR = 1.47, 95% CI 1.06-2.04, P = 0.021) and OS (HR = 1.64, 95% CI 1.11-2.43, P = 0.013). Post-NAC TILs escalation (low to high) conferred the worse prognosis versus sustained low TILs (iDFS: HR = 2.97, 95% CI 1.93-4.55, P < 0.001; OS: HR = 3.43, 95% CI 2.02-5.85, P < 0.001). Conversely, TILs reduction (high to low) correlated with improved survival over persistent high TILs (iDFS: HR = 0.51, 95% CI 0.30-0.86, P = 0.012; OS: HR = 0.54, 95%CI 0.31-0.96, P = 0.034).
CONCLUSION: In HR+/HER2- eBC, elevated pre-treatment TILs are independently associated with inferior survival outcomes, while chemotherapy-induced TILs reduction in residual disease correlates with significant prognostic improvement.

Keywords:  Biomarker dynamics; Breast cancer; Neoadjuvant chemotherapy; Prognosis; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1186/s13058-025-02150-2
Cancers (Basel). 2025 Oct 23. pii: 3411. [Epub ahead of print]17(21):

Targeted Hyaluronan Degradation Enhanced Tumor Growth Inhibition in Gastrointestinal Cancer Models.

Fulai Zhou, Guangmao Mu, Honglei Bi, Limin Chen, Zhengxia Zha, Ying Jin, Mark L Chiu.

  Background. The dense hyaluronan (HA)-rich stroma in solid tumors can prevent effective tumor growth inhibition by hindering drug delivery and immune cell infiltration. However, the degradation of HA alone by systemic delivery of hyaluronidase has not shown significant improvement of tumor growth inhibition. Objectives/Methods. In this study, we targeted hyaluronan degradation by using antibody-enzyme (AbEn) molecules by fusing antibodies to a recombinant human hyaluronidase (HYAL). Results. The AbEn molecules were stable, retained both antigen-binding and enzymatic activities, and demonstrated a prolonged serum half-life of 132 h in rodent models. In the HA-rich colorectal cancer model, the cancer-associated fibroblast (CAF)-directed AbEn, TAVO423 (FAP × LRRC15 × HYAL trispecific antibody) achieved greater intratumoral HA depletion resulting in superior tumor growth inhibition compared to untargeted HYAL. Furthermore, the combination of TAVO423 in combination with other solid tumor cell targeting modalities such as 5-fluorouracil (5-FU), anti-PD-L1 monoclonal antibody, a PD-L1 × CD3 bispecific T-cell engager (TCE), and a CD318-targeting antibody-drug conjugate (ADC) all demonstrated enhanced tumor growth inhibition (TGI) values of 49-67% as compared to the respective monotherapy TGI values of 1-28%. In addition, TAVO423 improved the antitumor response of a 5T4 × CD3 TCE with an increase in TGI from 73% to 92% in an in vivo HA-rich pancreatic cancer model. The CAF-targeted HA degradation mediated by TAVO423 also reversed immune exclusion by increasing the density of CD8+ tumor-infiltrating lymphocytes (TILs) by 6-9-fold and synergized with PD-1 blockade to enhance TGI from 33% to 51% in an in vivo immunocompetent EMT-6 breast cancer model. Conclusions. These findings demonstrated the broad potential of the modular AbEn platform for targeted HA degradation to overcome barrier entry in stromal HA-rich solid tumors.

Keywords:  FAP; LRRC15; hyaluronidase; solid tumor microenvironment; stromal hyaluronan

DOI:  https://doi.org/10.3390/cancers17213411
Transl Cancer Res. 2025 Oct 31. 14(10): 7170-7185

Clinical signiﬁcance of CD155 expression and correlation with immune cell infiltration in triple-negative breast cancer.

Yan Zhao, Jinlu Wang, Tongjun Sun, Sijuan Jiang, Zongyu Xie, Jingru Lai, Ganyu Sang, Xin Jin.

   Background: As a newly focused immune checkpoint protein in cancers, CD155 is a potential target in immunotherapy. Tumor microenvironment (TME) as a crucial regulatory factor in immunotherapy, also plays a significant role in the development and progression of triple-negative breast cancer (TNBC). This study aims to further clarify the relationship between the expression of CD155 and TME in TNBC.
Methods: We conducted a retrospective analysis of 182 patients with TNBC who underwent surgical treatment at The First Affiliated Hospital of Bengbu Medical University between January 2014 and December 2018. CD155, stromal tumor-infiltrating lymphocytes (sTILs), CD4, CD8, and CD163 expression levels in TNBC specimens were assessed by immunohistochemistry. We analyzed the expression of CD155, the degree of sTIL infiltration, the profiles of immune cell subsets, and their associations with clinicopathological characteristics and survival outcomes. At the same time, the relationship between CD155 expression, TNBC progression, and immune cell infiltration in the TME was evaluated using both the clinical samples and public datasets.
Results: Among the 182 TNBC patients, 131 (72.0%) were CD155 high expression, and 51 (28.0%) were CD155 low expression. CD155 expression was positively correlated with tumor diameter, lymph node metastasis, and Ki-67 status (all P<0.05). There were 112 patients (61.5%) with sTILs low infiltration and 70 patients (38.5%) with sTILs high infiltration. One hundred and twelve (61.5%) were identified with sTIL slow infiltration and 70 (38.5%) with sTILs high infiltration, sTILs were negatively correlated with lymph node metastasis (rs =-0.189, P=0.01) and positively correlated with Ki-67 status (rs =0.390, P<0.001). CD8+sTILs were negatively correlated with lymph node metastasis (rs =-0.240, P=0.001) and positively correlated with Ki-67 status (rs =0.367, P<0.001). CD4+sTILs were negatively correlated with lymph node metastases (rs =-0.184, P=0.01). CD163+sTILs were positively correlated with histological grade (rs =0.164, P=0.03) and Ki-67 status (rs =0.147, P=0.048). Spearman correlation analysis showed that CD155 expression level was positively correlated with CD163 expression level in TME (P<0.05). Univariate analysis showed that tumor size, histological grade, lymph node metastasis, sTILs content, CD8, CD4, CD163, and CD155 were correlated with disease-free survival (DFS) and overall survival (OS) (all P<0.05). DFS and OS. Multivariate analysis showed that tumor size, lymph node metastasis, CD8, CD163 and CD155 had significant effects on DFS (P<0.05), and lymph node metastasis, CD8, CD163 and CD155 had significant effects on OS (P<0.05). Kaplan-Meier survival curve showed that there were significant differences in DFS and OS among patients with high or low expression of CD8, CD4, CD163, sTILs, and CD155 (all P<0.05).
Conclusions: Overexpression of CD155 may contribute to the formation of the immunosuppressive TME mediated by M2 macrophages. CD155 overexpression introduced a worse relapse-free survival and OS and might be a potential immunotherapy target in TNBC patients.

Keywords:  CD155; Triple-negative breast cancer (TNBC); prognosis, tumor immunotherapy; tumor-infiltrating lymphocytes (TILs)

DOI:  https://doi.org/10.21037/tcr-2025-643
Oncologist. 2025 Nov 10. pii: oyaf368. [Epub ahead of print]

An early relapse prediction model based on pathological features following neoadjuvant immunotherapy for hepatocellular carcinoma.

Yanrui Pang, Xuelian Zhao, Xinxin Guo, Jing Han, Yuan Ji.

   BACKGROUND: The emergence of neoadjuvant immunotherapy has improved outcomes for hepatocellular carcinoma (HCC) patients, yet early postoperative recurrence remains a critical challenge. This study aimed to identify clinicopathological and immune microenvironment features associated with recurrence-free survival (RFS) and develop a predictive model for early recurrence in HCC patients undergoing neoadjuvant anti-PD-1 antibody therapy.
MATERIALS AND METHODS: Clinicopathological characteristics and immune microenvironment profiles were analyzed in 70 HCC patients treated with neoadjuvant anti-PD-1 antibody and 20 patients receiving transarterial chemoembolization (TACE). Key variables, including microvascular invasion (MVI), tumor capsule integrity, and immune cell infiltration, were evaluated. Statistical analyses included multivariate Cox regression, Kaplan-Meier survival analysis, and nomogram construction with internal validation to predict recurrence risk.
RESULTS: Foam cell response and tumor-infiltrating lymphocytes (TILs) were strongly linked to favorable immunotherapy responses. Patients without MVI, those with intact tumor capsules, and those exhibiting high CD4+ T cell density in central tumor regions demonstrated significantly prolonged RFS. A nomogram integrating these three factors achieved robust predictive accuracy for early recurrence stratifying patients into distinct risk groups.
CONCLUSIONS: This study highlights MVI absence, tumor capsule integrity, and CD4+ T cell infiltration as key predictors of RFS in HCC patients receiving neoadjuvant immunotherapy. The proposed nomogram provides a clinically actionable tool for early recurrence risk assessment, enabling personalized postoperative monitoring and adjuvant therapy strategies to improve survival outcomes.

Keywords:  Hepatocellular carcinoma; immunotherapy; neoadjuvant; nomogram; recurrence

DOI:  https://doi.org/10.1093/oncolo/oyaf368
ESMO Open. 2025 Nov 11. pii: S2059-7029(25)01750-8. [Epub ahead of print]10(12): 105881

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

T Lu, J Li.

DOI: https://doi.org/10.1016/j.esmoop.2025.105881
Front Immunol. 2025 ;16 1724025

Editorial: Cellular immunotherapy: transforming cancer treatment.

Yahia Moualla, Laura Belver.



Keywords:  CAR (chimeric antigen receptor); CIK (cytokine-induced killer) cells; TIL (tumor infiltrating lymphocytes); cell-based immunotherapies; engineered TCR T cells

DOI:  https://doi.org/10.3389/fimmu.2025.1724025
Acad Radiol. 2025 Nov 07. pii: S1076-6332(25)00957-2. [Epub ahead of print]

Performance of Machine Learning Models Based on Medical Imaging in Predicting the expression of PD-L1 and CD8+TILs in Thoracic cancer: A Systematic Review and Meta-Analysis.

Meixi Liu, Jie Gong, Yufen Liu, Fan Meng, Zihan Shi, Yan Cui, Lina Zhao.

   RATIONALE AND OBJECTIVES: Medical imaging integrated with artificial intelligence (AI) has demonstrated considerable potential in predicting the tumor immune microenvironment (TIME). However, the robustness of methodologies and predictive performance remains debated. This study systematically reviews and performs a meta-analysis to evaluate the advancements in AI-driven medical imaging for predicting the TIME in thoracic tumors, with a specific focus on Programmed Death-Ligand 1 (PD-L1) expression and CD8+ tumor-infiltrating lymphocytes (TILs). We hypothesize that medical imaging-based AI models can effectively predict key components of the tumor immune microenvironment in thoracic cancers, specifically PD-L1 expression and CD8+ TILs.
METHODS: Following PRISMA guidelines, we systematically searched PubMed, Cochrane, Embase, and Web of Science for studies published up to July 01, 2025. Studies evaluating AI-driven medical imaging for predicting thoracic tumor TIME were included. Diagnostic accuracy data were extracted, and a meta-analysis was conducted using a random-effects model to assess the predictive performance of AI models for PD-L1 expression and CD8+ TILs. Heterogeneity analysis and publication bias assessment were also performed.
RESULTS: A total of 68 studies were included, of which 25 were eligible for meta-analysis. The pooled area under the curve (AUC) for AI-driven medical imaging prediction of PD-L1 expression was 0.81 (95% CI: 0.78-0.85), with a sensitivity of 0.77 (95% CI: 0.74-0.80) and a specificity of 0.73 (95% CI: 0.71-0.76). For CD8+ TIL prediction, the pooled AUC was 0.86 (95% CI: 0.82-0.89), with a sensitivity of 0.81 (95% CI: 0.72-0.87) and a specificity of 0.81 (95% CI: 0.76-0.84). Subgroup analysis indicated that integrating multimodal imaging and deep learning models improved predictive performance. Nevertheless, considerable heterogeneity was observed among studies (I² > 75%).
CONCLUSION: AI-driven medical imaging exhibits strong predictive capability for thoracic tumor TIME, particularly in PD-L1 expression and CD8+ TIL prediction. However, significant interstudy heterogeneity limits the generalizability of current models. Future studies should prioritize multicenter, large-scale research, standardization of imaging feature extraction, and integration of biological mechanisms to improve the clinical applicability of AI models.

Keywords:  Artificial intelligence; CD8+ tumor-infiltrating lymphocytes; PD-L1; Radiomics; Thoracic tumors; Tumor immune microenvironment

DOI:  https://doi.org/10.1016/j.acra.2025.10.002
Front Immunol. 2025 ;16 1626581

Targeting asparagine potentiates anti-PD-L1 immunotherapy in gastric cancer by enhancing CD8+ T cell anti-tumor response.

Mingpai Ge, Longfei Wang, Bowen Zheng, Lu Zhan, Lu Cui, Han Wang, Enyuan Huang, Yuan Xu, Xusheng Chang, Zhaorui Liu, Jun Xu, Kai Yin.

   Introduction: Immunotherapy efficacy in gastric cancer (GC) is often constrained by the tumor microenvironment (TME), which is profoundly influenced by aberrant metabolism. Asparagine, an amino acid critical for neoplastic proliferation, also modulates CD8+ T cell metabolic programming. We investigated the impact of targeting asparagine on the GC immune microenvironment and its potential to synergize with anti-PD-L1 therapy.
Methods: The therapeutic efficacy of asparagine targeting was evaluated in GC tumor models. CD8+ T cell populations within the TME were analyzed by flow cytometry, while cytokine and chemokine levels (IFN-γ, GZMB, CXCL9, CXCL10) were quantified by ELISA. The effects on CD8+ T cell activation and antitumor function were assessed in vitro and in vivo. Synergistic efficacy with anti-PD-L1 therapy was evaluated in GC models, and the dependency on CD8+ T cells was confirmed via antibody-mediated depletion experiments.
Results: Targeting asparagine inhibited GC growth in vitro and in vivo, implicating immune system involvement. Mechanistically, asparagine targeting significantly increased the proportion of CD8+ T cells within the TME and upregulated the expression of IFN-γ, GZMB, CXCL9, and CXCL10. Furthermore, combining asparagine targeting with anti-PD-L1 therapy produced synergistic antitumor activity. This combined therapeutic effect was significantly attenuated by the depletion of CD8+ T cells.
Discussion: Our findings indicate that targeting asparagine promotes CD8+ T cell activation and infiltration, thereby remodeling the GC immune microenvironment to enhance host antitumor immunity. The combination of asparagine targeting with anti-PD-L1 therapy elicits potent, synergistic antitumor effects that are demonstrably dependent on CD8+ T cells. This study provides a strong rationale for targeting asparagine metabolism as a novel strategy to improve immunotherapeutic outcomes in GC.

Keywords:  CD8 T cell; TME (tumor microenvironment); asparagine; gastric cancer; immunotherapy; metabolism

DOI:  https://doi.org/10.3389/fimmu.2025.1626581
J Pathol Clin Res. 2025 Nov;11(6): e70059

B lymphocytes and tertiary lymphoid structures have a prognostic impact on penile squamous cell carcinoma.

Nicolette Zavillová, Petr Waldauf, Michaela Kendall Bártů, David Čapka, Jan Hojný, Zuzana Prouzová, Radoslav Matěj, Roman Zachoval, Jan Hrudka.

  Several prognostic markers, including tumor-infiltrating lymphocytes, which have been recently identified in penile squamous cell carcinoma (pSCC), have focused mostly on T cells. The prognostic role of B cells and tertiary lymphoid structures (TLSs) has not yet been sufficiently described. We examined whole tissue sections histopathologically for TLSs and immunohistochemically for CD20 and CD138. The B-cell immunoscore (B-IS) divided the cohort into five categories based on the expression of these two B-cell/plasma cell markers (CD20 and CD138, respectively). Patients with fewer TLSs had worse overall survival (OS) [hazard ratio (HR) = 2.17; 95% CI: 0.94-5; p = 0.069]. A significant association was identified between a high TLS diameter and the presence of a lymphocytic infiltrate [odds ratio (OR) = 2.2442; 95% CI: 1.1022-4.55; p = 0.0208]. Patients with low B-IS (HR = 1.89, 95% CI: 1.18-3.03, p = 0.008), a low number of CD20+ cells in the tumor center (HR = 1.67, 95% CI: 1.04-2.7, p = 0.035), and a low number of CD20+ cells at the tumor invasion front (HR = 1.69, 95% CI: 1.06-2.78; p = 0.028) had significantly worse OS. High B-ISs were strongly associated with a mutated p53 profile detected by immunohistochemistry (OR = 4.76, 95% CI: 1.32-25, p = 0.011), low T-cell immunoscores (OR = 0.49; 95% CI: 0.23-1.03; p = 0.051), and brisk lymphocytic infiltration (OR = 2.0417, 95% CI: 1.01-4.76; p = 0.037). High CD20+ cell counts at the invasion front were associated with histological grade 3 disease (OR = 2.44, 95% CI 1.15-5.26, p = 0.015). An association was also observed between low B-IS and mutations in KMT2D (OR 0.31, 95% CI: 0.07-1.21, p = 0.057) and EGFR (OR = ∞, 95% CI: 0.86-∞, p = 0.053). In conclusion, high numbers of tumor-infiltrating B cells within TLSs represent a favorable prognostic marker in pSCC. These findings emphasize the need to identify novel microscopic prognostic markers during pathological assessment to guide early and appropriate therapeutic strategies.

Keywords:  B‐cell immunoscore (B‐IS); CD138; CD20; penile; penile squamous cell carcinoma (pSCC); penis; prognosis; tertiary lymphoid structures (TLSs); tumor‐infiltrating lymphocytes (TILs)

DOI:  https://doi.org/10.1002/2056-4538.70059
J Adv Res. 2025 Nov 08. pii: S2090-1232(25)00904-X. [Epub ahead of print]

PRDM15 inhibits responses of Tissue-Resident memory T cells by activating PVR/TIGIT axis to mediate gastric cancer immunosuppression.

Xinyao Zhang, Jinsen Zheng, Hantao Guo, Tiantian Song, Bin Xiong.

   INTRODUCTION: Gastric cancer (GC) has shown relatively poor responses to existing immune therapies. The extensive infiltration of tissue-resident memory T cells (TRM) in tumor microenvironment (TME) is associated with better Overall Survival (OS) in patients treated with immune checkpoint inhibitors (ICIs). However, the precise roles of TRM cells in cancer immunity and responses to ICIs in GC remain poorly understood.
OBJECTIVES: We found that the TRM cells representing the majority of tumor-infiltrating lymphocytes and expressing high level of immune checkpoint TIGIT in GC tissue. This study aims to elucidate the mechanisms through which GC cells modulate TRM cells by PVR/TIGIT axis to facilitate immune evasion.
METHODS: The immune status of GC was evaluated by quantifying T cell subsets in GC tissues through flow cytometry. The biological functions and molecular mechanisms by which the oncogenic factor PRDM15 mediates tumor immune evasion were investigated through the PVR/TIGIT axis using transcriptome sequencing, Chromatin immunoprecipitation (ChIP) assay and Co-immunoprecipitation assay. The therapeutic potential of PRDM15/PVR/TIGIT was analyzed using tumor-bearing models.
RESULTS: We confirmed that PRDM15 promotes the transcription of PVR which is the ligand of TIGIT in GC cells. Aberrantly high expression of PRDM15 in GC tissues was associated with higher TNM stages and T cell immunosuppressive state in GC patients. PRDM15 was found to upregulate the proliferation, invasion and migration of GC cells. When co-cultured with TRM cells with high TIGIT expression, PRDM15 activated the PVR/TIGIT axis to inhibit TRM cells activation by upregulating PVR expression in GC cells. Mechanistically, PRDM15 recruited the histone methyltransferase complex PRMT5/Mep50/WDR5 to activate PVR transcription.
CONCLUSION: This study demonstrated that PRDM15 in GC cells could recruits the histone methyltransferase complex PRMT5/Mep50/WDR5 to promote PVR transcription, thereby activating the PVR/TIGIT axis, which inhibits TRM cells activation and mediates immune escape and GC progression.

Keywords:  Epigenetic modification; Gastric cancer; Immune escape; PRDM15; PVR/TIGIT; Tissue-resident memory T cells

DOI:  https://doi.org/10.1016/j.jare.2025.11.009
Br J Dermatol. 2025 Nov 10. pii: ljaf450. [Epub ahead of print]

Harnessing Arginase-2-specific CD8+ T cells to target immunosuppressive Cutaneous T cell Lymphoma.

Thomas Landkildehus Lisle, Stine Emilie Weis-Banke, Shamaila Munir Ahmad, Morten Orebo Holmström, Thy Viet Luu, Terkild Brink Buus, Leon Eyrich Jessen, Christoffer Dellgren, Torben Barington, Özcan Met, Niels Ødum, Mads Hald Andersen.

BACKGROUND: Arginase-2 (ARG2) is a metabolic enzyme that reduces local L-arginine levels in the tumor microenvironment, impairing T-cell function and suppressing antitumor immunity. We previously identified proinflammatory CD8+ T cells that recognize an ARG2-derived peptide presented by HLA-B8. These ARG2-specific CD8+ T cells, found in both healthy donors and cancer patients, selectively targeted autologous regulatory T cells (Tregs) and cancer cells with high ARG2 expression. In advanced cutaneous T-cell lymphoma (CTCL), malignant T cells have been reported to adopt immunosuppressive features resembling those of Tregs.
OBJECTIVES: To determine whether malignant CTCL cells express high levels of ARG2, similar to Tregs, and whether they can be targeted by ARG2-specific CD8⁺ T cells as a novel immunotherapeutic strategy.
METHODS: ARG2 expression was analyzed in eight CTCL cell lines by western blotting and in CTCL patient lesions using publicly available single-cell RNA sequencing datasets. Immunosuppressive features of the cell lines were evaluated by measuring IL-10 and TGF-β secretion, assessing the expression of immunoregulatory surface proteins, and testing their ability to suppress IFN-γ production in activated T cells. The SeAx cell line was transfected with an HLA-B8-encoding plasmid and used as target cells for ARG2-specific CD8⁺ T cells in IFN-γ ELISPOT assays. To confirm ARG2-dependent T-cell recognition, we modulated ARG2 expression through overexpression and CRISPR-Cas9-mediated knockdown.
RESULTS: ARG2 expression was highly heterogeneous across both CTCL cell lines and malignant T cells from CTCL patient lesions. The CTCL cell lines also exhibited diverse immunosuppressive features, including IL-10 and TGF-β secretion, and suppressed IFN-γ production by activated T cells. SeAx cells displayed moderate ARG2 levels and were selected as a model to assess targeted recognition of CTCL cells. Following HLA-B8 transfection, ARG2-specific CD8+ T cells from several donors recognized and responded to SeAx cells, as demonstrated by increased IFN-γ secretion. Recognition required both ARG2 and HLA-B8, as responses were enhanced by ARG2 overexpression, diminished by CRISPR-Cas9-mediated knockdown, and absent in mock-transfected controls.
CONCLUSIONS: This study provides the first evidence that malignant CTCL cells can be targeted by ARG2-specific CD8⁺ T cells, highlighting ARG2 as a promising immunotherapeutic target in CTCL.

DOI: https://doi.org/10.1093/bjd/ljaf450
J Pathol. 2025 Nov 15.

Novel growth pattern-specific digital marker of TILs improves stratification of lung adenocarcinoma patients.

Arwa AlRubaian, Ayesha Azam, Nasir M Rajpoot, Shan E Ahmed Raza.

  Lung adenocarcinoma (LUAD) is one of the most prevalent forms of cancer and continues to be associated with high mortality rates, despite recent advances in cancer therapy. Effective risk stratification is critical for guiding treatment decisions and improving our understanding of disease mechanisms. However, current prognostic approaches face considerable limitations. Growth pattern-based grading serves as a prognostic indicator of tumour aggressiveness, but is inherently subjective and prone to a high degree of variability among observers. Other well-established prognostic indicators, such as tumour infiltrating lymphocytes (TILs) and stromal TILs (sTILs) scores, provide valuable prognostic information but require labour-intensive assessment. The pronounced heterogeneity of LUAD further complicates prognosis and underscores the need for robust, integrative biomarkers that capture both the morphological and immunological characteristics of the tumour. To address this need, we propose an AI-based growth-pattern-specific TILs (GPS-TILs) marker that quantifies TILs and sTILs within each growth pattern separately. By integrating morphological information from the tumour growth patterns and immune microenvironment data from TILs, we demonstrate that the proposed GPS-TILs marker improves patient stratification. We evaluated the prognostic utility of GPS-TILs using survival analysis with Cox proportional hazards models in a cross-validation setting using The Cancer Genome Atlas LUAD (TCGA-LUAD) cohort. Our findings revealed that GPS-TILs offers strong prognostic value for overall survival (p < 0.0001, C-index = 0.59), outperforming conventional TIL-based measures and morphology-based stratification approaches. These results highlight the potential of GPS-TILs as a more objective and effective tool for improving patient risk stratification in LUAD. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords:  STILs; TILs; artificial intelligence; histological growth patterns; histology images; lung adenocarcinoma; lymphocytes; survival analysis; tumour microenvironment

DOI:  https://doi.org/10.1002/path.6498
J Leukoc Biol. 2025 Nov 07. pii: qiaf160. [Epub ahead of print]

Method for generation and ex vivo expansion of genetically edited mouse Tregs.

Yosef Gilad, Adam M Dean, Yan Xia, Sang Jun Han, David M Lonard, Bert W O'Malley.

  Regulatory T cells (Tregs) play a crucial role in the immune system, and their dysfunction can lead to the development of autoimmune conditions. In cancer, tumors frequently hijack the immunosuppressive function of Tregs to evade immune responses. Due to their central role in key pathological processes, Tregs have gained increasing attention as promising targets for various clinical applications. However, their relative scarcity (∼5-10% of CD4+ T cells) and instability presents a technical challenge for research and therapeutic development. In congenic animal models used to investigate autologous cell transfer based therapies, this challenge is even greater, as Treg donor animals may only be able to provide cells to a small number of recipient mice. Here we present an optimized protocol for ex vivo editing and expansion of mouse Tregs (mTregs). Since a recent study demonstrated the anti-cancer potential of SRC-3 KO mTregs, we use them here as a case study.

Keywords:  CRISPR-Cas9; Cell therapy; Gene editing; SRC-3; Tregs

DOI:  https://doi.org/10.1093/jleuko/qiaf160
Front Immunol. 2025 ;16 1677548

Reprogramming the tumor microenvironment to boost adoptive T cell therapy.

Maria Fernanda Meza Pacheco, Lee-Hwa Tai.

  Adoptive T cell therapies (ACT) have revolutionized the management of hematologic malignancies; however, their efficacy in solid tumors remains limited. Accumulating evidence implicates the tumor microenvironment (TME) - a highly complex and immunosuppressive niche as a major barrier to their effectiveness. In this review, we propose that the next generation of ACT will require a fundamental shift from a reductionist focus on T cell engineering alone to an integrated approach that considers the interactions between immune cells and the TME. A comprehensive literature review identified several emerging strategies to enhance the efficacy of ACT, including reprogramming tumor vasculature, repolarizing immunosuppressive myeloid and stromal cells, leveraging oncolytic viruses to remodel antigen presentation, inducing acute sterile inflammation, and targeting the physical properties of the extracellular matrix. While many of these approaches remain in early-stage development, some have already progressed to clinical trials, indicating their potential for clinical translation. Additionally, we found that conventional therapies, such as surgery, chemotherapy, and radiotherapy, can be strategically integrated with ACT to improve therapeutic outcomes. These findings highlight a shift in the field toward more integrative approaches. Future advances will likely depend on reprogramming the TME to support T cell persistence and functions. Addressing these interconnected challenges will require closer collaboration between immunology, oncology, and bioengineering disciplines.

Keywords:  CAR (chimeric antigen receptor) T-cell therapy; adoptive T cell immunotherapy; immunomodulation; immunotherapy; oncology; tumor infiltrating lymphocyte; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1677548
Geroscience. 2025 Nov 15.

Targeting the HMGB1-IL32 pathway to alleviate T cell exhaustion in epithelial ovarian cancer.

Ankita Murmu, Balázs Győrffy.

  Single-cell gene expression data can provide insights into cell-cell communication, enabling us to understand the interaction between cancer cells and microenvironmental cells. Here, our goal was to unravel how intercellular communication influences terminally exhausted CD8 + T cells in the ovarian tumor microenvironment. We processed and integrated ovarian cancer scRNA-Seq samples and delineated distinct cellular populations based on the expression patterns of established canonical marker genes. We performed a pseudotime trajectory analysis of CD8 + T cells and analyzed the communication of ovarian cancer cells with terminally exhausted CD8 + T cells. Investigating cell lineage and inferring pseudotimes revealed the transition of the CD8 + T cells from naïve-like to six different end-states, with central memory (35%), effector memory (31%), and terminally exhausted (25%) CD8 + T cells being the most abundant CD8 + T cell subtypes. Cell-cell communication analysis identified the HMGB1-HAVCR2 ligand-receptor pair mediating communication from ovarian cancer cells to terminally exhausted CD8 + T cells. High Mobility Group Box 1 (HMGB1) was identified as a key ligand expressed in ovarian cancer cells influencing the IL32 expression in terminally exhausted CD8 + T cells. The signaling path from HMGB1 to IL32 revealed NFKB1 as the most significant signaling mediator and TP53 as the most significant transcriptional regulator via which HMGB1 influenced IL32 expression in CD8 + T cells. The HMGB1-IL32 signaling pathway identified in our analysis can serve as a therapy target for a new generation of adjuvant therapy designed to suppress and disrupt tumor cells' influence on the microenvironment and enhance immunotherapy efficiency.

Keywords:  Drug discovery; Epithelial ovarian cancer; Immunotherapy; Pharmacology; Targeted therapy

DOI:  https://doi.org/10.1007/s11357-025-01963-5
Research (Wash D C). 2025 ;8 0851

SPP1+ TAM: CD8+ T Cell Crosstalk Associates with Blocking Radiotherapy Efficacy in Lung Cancer.

Yuzhao Jin, Yuan Zhuang, Peng Luo, Xiaojie Zhang, Jinhua Luo, Yifei Ma, Dandan Guo, Na Hang, Qing Li, Zhijun Shen, Zhao Xie, Ruiqing Gao, Chenyu Gao, Ling Wang, Wenjun Mao, Bufu Tang, Songhua Cai.

Radiotherapy (RT) is a cornerstone treatment for non-small cell lung cancer (NSCLC), but its efficacy is often limited by immune suppression in the tumor microenvironment. In this study, we identified SPP1 as a key factor up-regulated after RT, mainly expressed by immunosuppressive macrophages. Single-cell RNA sequencing and in vivo models showed that SPP1+ macrophages inhibit CD8+ T cell infiltration and correlate with poor prognosis. Targeting SPP1 in macrophages enhanced RT efficacy, reduced tumor burden, and restored antitumor immunity. In summary, combining RT with SPP1+ macrophage-targeted intervention may serve as a promising strategy to overcome immune-mediated radioresistance and enhance therapeutic efficacy in NSCLC.

DOI: https://doi.org/10.34133/research.0851
Pathol Oncol Res. 2025 ;31 1612229

Synergistic changes in bystander CD8 and conventional CD4 T cells during neoadjuvant chemoimmunotherapy for non-small cell lung cancer reveal treatment response.

Li Wu, Liying Yang, Jian Sun, Miaoqing Zhao, Jiaxiao Geng, Fanghan Cao, Qianhui Chen, Yushan Yan, Hao Yang, Xiaorong Sun, Ligang Xing.

   Objective: We analyzed changes in intratumoral CD8+ and CD4+ T-cell subpopulations following neoadjuvant chemoimmunotherapy in non-small cell lung cancer. We then assessed whether these alterations favored better outcomes and explored their association with the tumor microenvironment.
Methods: Paired pre- and post-treatment samples from 32 patients with non-small cell lung cancer who underwent neoadjuvant chemoimmunotherapy at Shandong Cancer Hospital (January 2021-June 2023) were analyzed retrospectively. A quantitative analysis of tumor cells and their microenvironment was performed using a tissue microarray and a multiplex immunofluorescence technique. The analysis was based on the number of cells per thousand nucleated cells. Patients exhibiting a major pathologic response were classified as responders. The delta parameter (post-treatment minus pre-treatment) was utilized to assess changes in these indicators, and associations with treatment response were identified using the Wilcoxon Signed-Rank test and logistic regression analyses.
Results: Of the 32 patients, 59.38% were classified as responders. Across all patients, neoadjuvant chemoimmunotherapy significantly reduced the densities of dysfunctional CD8+ resident memory T cells and cytotoxic and dysfunctional CD8+ bystander T cells, while conventional CD4+ T cells increased significantly. Similar trends were observed in the response group. In the non-response group, only cytotoxic CD8+ bystander T cells were reduced in number. Logistic regression analysis revealed that a high delta conventional CD4+ T cells is more favorable for MPR (OR = 0.13, p = 0.038), exhibiting a similar trend to changes in HIF-1α (p = 0.049).
Conclusion: Alterations in specific CD8+ and CD4+ T-cell subpopulations during neoadjuvant chemoimmunotherapy may favor better outcomes and are potentially associated with tumor hypoxia. These findings provide a new perspective on developing strategies to improve treatment sensitivity in non-small cell lung cancer.

Keywords:  bystander CD8; conventional CD4; hypoxia inducible factor-1α; neoadjuvant chemoimmunotherapy; non-small cell lung cancer

DOI:  https://doi.org/10.3389/pore.2025.1612229
Blood Cancer Discov. 2025 Nov 14.

Composition and functional state of T and NK cells in the extramedullary myeloma tumor microenvironment.

Anjana Anilkumar Sithara, Veronika Kapustova, David Zihala, Ondrej Venglar, Daniel Bilek, Moutaz Helal, Mara John, Eva Radova, Lucie Broskevicova, Jan Vrana, Gabriela Havlova, Ludmila Muronova, Tereza Popkova, Jana Mihalyova, Hana Plonkova, Serafim Nenarokov, Kamlesh Bisht, Hongfang Wang, Helgi Van de Velde, Sandra Charvatova, Ivo Demel, Michal Kascak, Milan Navratil, Martin Havel, Juli Bago, Michal Simicek, Angela Riedel, Leo Rasche, Tereza Sevcikova, Ola Landgren, Roman Hájek, Tomas Jelinek.

Extramedullary multiple myeloma (EMM) is a high-risk feature of multiple myeloma (MM) associated with increased resistance to treatments, including modern immunotherapies, and shorter survival. Composition and functional state of immune cells within the EMM tumor microenvironment (TME) remain poorly understood. Using single-cell RNA sequencing, flow cytometry, and spatial transcriptomics, we revealed significant differences in the EMM TME compared to MM bone marrow. T and NK cells were verified as the most abundant immune subsets in the EMM TME. Compared to the bone marrow counterparts, we found these tumors to have a significantly reduced effector-to-tumor cell ratio, significantly lower number of CD4⁺ T cells, and increased proportion of regulatory CD16⁻ NK cells. We observed a high proportion of exhausted, tumor-reactive CD8+ T cells in roughly half of EMM tumors. Furthermore, we identified elevated expression of immune checkpoints, such as PD-1 on CD8⁺ T cells and KLRC1 (NKG2A) on CD16⁻ NK cells.

DOI: https://doi.org/10.1158/2643-3230.BCD-25-0170
Cancer Res. 2025 Nov 11.

Response to Immune Checkpoint Blockade is Enhanced in the Presence of Hematopoietic TET2 Inactivation.

Vincent Rondeau, Suraj Bansal, Marco M Buttigieg, Andy G X Zeng, Darryl Y Chan, Michelle Chan-Seng-Yue, Liqing Jin, Jessica McLeod, Meghan Kates, Elisa Donato, Patrick Stelmach, Caitlyn Vlasschaert, Yitong Yang, Aarushi Gupta, Sofia Genta, Enrique Sanz-Garcia, Liran Shlush, Mauricio Ribeiro, Marcus O Butler, Sagi Abelson, Mark D Minden, Samuel D Saibil, Steven M Chan, Michael J Rauh, Andreas Trumpp, John E Dick, Robert J Vanner.

Somatic mutations inactivating TET2 are among the most common drivers of clonal hematopoiesis (CH). TET2 inactivation is associated with monocyte-derived inflammation and improved chimeric antigen receptor T cell function, suggesting it might also impact immunotherapy response. Here, we found that hematopoietic Tet2 mutation in mouse models enhanced the immune checkpoint blockade (ICB) response, which required the combined presence of phagocytes, CD4+, and CD8+ T cells. The effect was lost with myeloid- or T-cell restricted Tet2 inactivation or in mice with 20% Tet2-mutant hematopoiesis. Mechanistically, in Tet2-mutant tumor-infiltrating leukocytes (TILs), ICB preferentially restricted cell states linked to tumor progression while inducing anti-tumor states. Tet2-mutant monocytes activated costimulatory programs, while Tet2-mutant T cells showed enhanced T cell memory signatures, alongside decreased exhaustion and regulatory phenotypes. Clinically, tumors from colorectal cancer and melanoma patients with TET2 driver mutation-CH (TET2-CH) showed enhanced immune infiltration, inflammation, and T cell activation. In melanoma patients treated with ICB, TET2-CH was associated with 6-fold greater odds of clinical benefit. Collectively, this work demonstrates that hematopoietic TET2 inactivation primes leukocytes for anti-tumor states associated with immunotherapy response and provides a potential biomarker for personalized therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3329
Sci Rep. 2025 Nov 13. 15(1): 39822

Diagnostic accuracy of interferon-gamma release assay and mucosal-associated invariant T cells in spinal tuberculosis.

Korawish Mekariya, Pisanukiet Saneewong Na Ayutthaya, Akkaraporn Naowanirut, Artit Wongsa, Boonrat Tassaneetrithep, Wiwit Tantibhedhyangkul, Popchai Ngamskulrungroj, Sorranart Muangsomboon, Pipat Cheiwvit, Sirichai Wilartratsami, Panya Luksanapruksa, Nasuda Danchaivijitr, Kitidete Boonchai, Apisit Rattanatanasarn, Monchai Ruangchainikom.

  Conventional diagnostic methods for tuberculous spondylodiscitis (TS) require tissue biopsy, which can delay diagnosis. Immunodiagnostic approaches, including interferon-gamma release assays (IGRAs), have shown potential for improving TS diagnosis. Recent advancements have also identified the potential role of mucosal-associated invariant T (MAIT) cells as biomarkers for TB infection. This study aims to evaluate the diagnostic performance of IGRA using the QuantiFERON-TB Gold In-Tube test (QFT-GIT) and MAIT cell analysis for diagnosing TS. Sixty-five patients suspected TS were prospectively enrolled, of whom 24 (37%) were categorized as confirmed TS. QFT-GIT demonstrated a sensitivity of 82.61% and specificity of 77.78%. No significant differences were found in the proportion of MAIT cells, CD4 + MAIT, CD8 + MAIT, and Double negative (CD4- CD8-) MAIT when compared between TS and non-TS patients. However, The MAIT cell population in CD8 + T lymphocytes subset was significantly higher in patients with TS (p = 0.0081). MAIT cell percentage > 2.63% in CD8 + T cell subset demonstrated fair discriminative ability, with an AUC of 0.746, sensitivity of 90.5%, and specificity of 51.4%. Combining QFT-GIT and the proportion of MAIT cells in CD8 + T cells subset improved specificity to 96.9%. These findings highlight the potential of these tests as promising, non-invasive diagnostic tools for differentiating TS in spondylodiscitis patients, especially when tissue diagnosis is not feasible.

Keywords:  Diagnostic tests; Interferon-gamma release assays; MAIT cells; Mucosal-Associated invariant t cells; Spinal tuberculosis; Spondylitis tuberculous

DOI:  https://doi.org/10.1038/s41598-025-23408-x
J Immunother Cancer. 2025 Nov 13. pii: e012858. [Epub ahead of print]13(11):

TAMs-mediated resistance to oncolytic virus M1 in solid tumors.

Xuanming Liang, Jingjie Li, Jiehong Chen, Chaoxin Chen, Honghui Li, Caixin Yan, Cui Guo, Yu Han, Wenfeng Liu, Ke Sai, Yuan Lin, Guangmei Yan, Wenbo Zhu, Ying Liu.

   BACKGROUND: Oncolytic virus M1 (OVM), a naturally occurring alphavirus, has demonstrated potent antitumor activity in various solid tumor models by inducing immunogenic cell death and activating CD8+ T cells. However, its in vivo efficacy varies widely, and resistance mechanisms remain poorly understood. Tumor-associated macrophages (TAMs), key immunosuppressive cells within the tumor microenvironment, may limit OVM therapeutic potential.
METHODS: We investigated the role of TAMs in OVM resistance using multiple syngeneic mouse tumor models (MC38 colorectal cancer, KPC1199 pancreatic cancer, RM1 prostate cancer, and B16F10 melanoma). TAMs were depleted using clodronate liposomes or CSF1R (Colony Stimulating Factor 1 Receptor) antibodies. Flow cytometry, mass cytometry, quantitative reverse transcription-PCR, and transcriptomic sequencing were employed to assess TAMs infiltration, viral load, and immune responses. CD8+ T cells were selectively depleted to determine their functional relevance.
RESULTS: TAMs infiltration was positively correlated with resistance to OVM across tumor models. Depletion of TAMs increased intratumoral viral load and promoted accumulation of GZMB+ CD8+ T cells. RNA sequencing analysis revealed upregulation of antiviral and T-cell immune pathways in TAMs-depleted tumors. Importantly, the therapeutic benefit of TAMs depletion was abrogated on CD8+ T-cell depletion, confirming their essential role in mediating OVM efficacy. In both OVM non-responsive and responsive tumors, TAMs depletion enhanced OVM-mediated tumor suppression and survival.
CONCLUSIONS: TAMs, particularly M1-like subsets, play a critical role in mediating resistance to OVM therapy by reducing viral persistence and suppressing CD8+ T-cell responses. Targeting TAMs significantly improves the antitumor efficacy of OVM in solid tumors. These findings support the development of TAMs-targeted combination strategies to optimize oncolytic virotherapy.

Keywords:  Immunotherapy; Macrophage; Oncolytic virus; Tumor microenvironment - TME; Virology

DOI:  https://doi.org/10.1136/jitc-2025-012858
J Theor Biol. 2025 Nov 08. pii: S0022-5193(25)00294-2. [Epub ahead of print] 112310

Mathematical modelling of tumor-immune interactions in breast cancer.

Haifeng Zhang, Chenghang Li.

  The dynamic interplay between tumors and immune system is pivotal to the progression of breast cancer. To systematically investigate how interactions between tumor cells and immune cells shape breast cancer evolution, we developed a mathematical model that incorporates tumor cells, dendritic cells (DCs), natural killer (NK) cells, regulatory T cells (Tregs) and CD8+ T cells. We first established analytical conditions for the local stability of the tumor-free equilibrium, identifying key constraints on tumor growth imposed by immune activity. The existence of a positive equilibrium solution further suggests the potential coexistence of tumor and immune cells. Numerical simulations demonstrate that effective tumor control is achieved under a high baseline level of CD8+ T cell precursors coupled with a low level of regulatory T cell precursors. These results highlight the important role of balancing immunostimulatory and immunosuppressive forces within the tumor microenvironment. Through bifurcation analysis, we identified regimes of bistability in which both high-tumor and low-tumor equilibria coexist with dynamic features that may underlie divergent clinical outcomes and present a critical challenge for clinical therapeutic intervention. Moreover, simulations of tumor-immune dynamics in virtual cohorts reveal that tumor control hinges on CD8+ T cell infiltration, whereas regulatory T cell abundance is a potent predictor of immune escape. Finally, we formulated an optimal control framework to design adaptive CD8+ T cell injection protocols. Numerical solutions demonstrate that such optimized strategies achieve superior tumor reduction compared with constant dosing, despite using the same total injection dose of CD8+ T cells and identical treatment intervals. Collectively, our findings provide a mechanistic understanding of breast cancer progression and establish a theoretical foundation for developing personalized therapeutic strategies to optimize clinical outcomes.

Keywords:  Breast cancer; Mathematical model; Numerical simulation; Optimal control; Sensitivity analysis

DOI:  https://doi.org/10.1016/j.jtbi.2025.112310
Cell Mol Immunol. 2025 Nov 14.

FOXO1-driven metabolic reprogramming of hematomal CD8+ T cells drives the expansion of perihematomal edema following intracerebral hemorrhage.

Jie Lin, Honglei Ren, Youliang Wang, Hanzhi Yu, Zhili Chen, Xintong Yu, Zhuyu Gao, Yan Zheng, Quanhong Wu, Yizhe Zhang, Qijian Lin, Rui Li, Decai Tian, Zhigang Cai, Qiang Liu, Ying Fu.

  Intracerebral hemorrhage (ICH) causes hematoma formation, leading to PHE, which is associated with leukocyte mobilization and increased inflammation at the site of brain injury. However, the fate of accumulated leukocytes within the hematoma and their impact on PHE expansion remain unknown. We performed single-cell immune profiling of hematoma cells from patients with acute ICH and reported a distinct phenotypic transformation of CD8+ T cells within the hematoma during the first 24 h after onset. In addition to enhanced IFN-γ production and migration capacity, these CD8+ T cells displayed remarkable glycolytic signatures. The metabolic fitness and functional reprogramming of hematomal CD8+ T cells are associated with the transcription factor FOXO1. Single-cell profiling of brain-infiltrating CD8+ T cells within the perihematomal tissues of ICH patients and cell culture assays revealed their capacity to activate microglia via the production of IFN-γ. Furthermore, the removal of hematomal CD8+ T cells reduced neuroinflammation, PHE expansion and neurological deficits in ICH mice. Thus, CD8+ T cells undergo metabolic and functional reprogramming within the hematoma during the acute phase of ICH, which contributes to PHE formation and neurological deterioration.

Keywords:  CD8+ T cells; Hematoma; Intracerebral hemorrhage; Neuroinflammation; Perihematomal edema

DOI:  https://doi.org/10.1038/s41423-025-01363-x
Transl Cancer Res. 2025 Oct 31. 14(10): 7358-7373

CXCR3 enhanced murine chimeric antigen receptor T cells in the treatment of solid tumors.

Xiangzhi Zhang, Luyu Zhu, Qiang Wang, Qinggang Xu, Xiaoyan Wang, Feng Yu.

   Background: Chimeric antigen receptor T cell (CAR-T) therapy has achieved remarkable success in the treatment of hematologic malignancies, but its efficacy against solid tumors remains limited. This limitation primarily arises from the physical and molecular barriers that restrict CAR-T infiltration. The CXCL10-CXCR3 axis plays a critical role in mediating immune cell migration. Notably, elevated CXCR3 expression in solid tumors is correlated with improved immune infiltration and patient survival. Furthermore, the downregulation of CXCR3 in CD8+ T cells was observed in tumor microenvironments, limiting their ability to infiltrate tumors. Therefore, we hypothesize that CXCR3-modified CAR-T will exhibit enhanced tumor infiltration capacity, thereby improving the therapeutic efficacy of CAR-T therapy against solid tumors.
Methods: We constructed murine CAR-Ts (mCAR-Ts) targeting EGFRvIII (a tumor-specific antigen) and overexpressing CXCR3, which we named EGFRvIII·mCAR-T-CXCR3 cells. These cells were functionally characterized by in vitro cytotoxicity and chemotaxis assays. The tumor suppression efficacy was further evaluated in immunocompetent mice bearing subcutaneous tumors. Immunohistochemical experiments were performed to evaluate the in vivo antitumor mechanisms of EGFRvIII·mCAR-T-CXCR3 cells.
Results: The EGFRvIII·mCAR-T-CXCR3 cells showed enhanced cytotoxic activity and CXCL10-directed migration in vitro. In the murine tumor models, the CXCR3-modified CAR-Ts showed significantly improved tumor suppression compared to the controls, as well as increased intratumoral T-cell infiltration.
Conclusions: CXCR3 overexpression potentiates the anti-tumor capacity of CAR-Ts in solid tumors by enhancing tumor infiltration. This strategy provides a promising approach for overcoming the current limitations of CAR-T therapy.

Keywords:  CXCR3; Chimeric antigen receptor T cell therapy (CAR-T therapy); chemotaxis; immunocompetent model; solid tumors

DOI:  https://doi.org/10.21037/tcr-2025-1920
Immunity. 2025 Nov 11. pii: S1074-7613(25)00472-8. [Epub ahead of print]58(11): 2621-2623

Fermenting T cell stemness for cancer immunity.

Hocheol Shin, Joon Seok Park.

Gut microbial metabolites modulate immune responses to tumors. In this issue of Immunity, Bachem et al.1 demonstrate that microbiota-derived butyrate cooperates with the transcription factor Foxo1 to promote CD8+ T cell stemness and enhance responsiveness to immune checkpoint inhibitors in melanoma.

DOI: https://doi.org/10.1016/j.immuni.2025.10.018
iScience. 2025 Nov 21. 28(11): 113680

Multi-parametric profiling of IL-7-augmented GD2.CART products in a phase 1 clinical trial.

Sarah Schulenberg, Martí Farrera-Sal, Michelle Loeser, Lukas Ehlen, Stephan Schlickeiser, Samira Picht, Lena Peter, Marco Mai, Candise L Tat, Jacqueline Keye, Desiree Kunkel, Frank Lin, Cliona M Rooney, Bilal Omer, Michael Schmueck-Henneresse.

  CAR T cell (CART) therapy holds promise for cancer treatment, but heterogeneity among products limits clinical effectiveness, making systematic profiling essential to identify predictors of success. Recently, a phase 1 clinical trial investigated whether a constitutively active IL-7 receptor (C7R) could safely improve the function and persistence of GD2-directed CARTs (GD2.CARTs) in pediatric patients with high-grade CNS tumors. We analyzed infusion products from trial participants using a custom-designed 33-color full spectrum flow cytometry (FSFC) panel combined with an image-based tumor killing assay to characterize CART products and evaluate the impact of C7R on GD2.CART performance. Patient-specific variations in T cell composition were linked to therapeutic success, with C7R co-expression enhancing the functional phenotype of GD2.CARTs compared to CAR-only products. Unsupervised clustering identified CD8+ T cells associated with clinical responses, marked by activation, infiltration, resilience, and cytotoxicity. Our FSFC-based profiling approach reveals determinants of CART efficacy and supports strategies to optimize adoptive immunotherapy.

Keywords:  Health sciences; Immunology; Laboratory medicine; Medicine; Oncology

DOI:  https://doi.org/10.1016/j.isci.2025.113680
Front Immunol. 2025 ;16 1607471

Multi-compartment immune cell profiling highlights the prognostic relevance of CD127+ CD8+ T cells for patients with high-grade serous ovarian cancer.

Rebecca Rothe, Antje Tunger, Theresa Link, Xixi Lai, Jan Dominik Kuhlmann, Pauline Wimberger, Marc Schmitz, Rebekka Wehner.

  Ovarian cancer (OC) is a heterogeneous tumor entity with accumulated ascitic fluid in the peritoneal cavity, especially in advanced tumors. In general, a high immune cell infiltration has a favorable effect on OC patients' outcomes. However, the composition of immune cells within the individual compartments of OC-associated locations may differ in their impact on patient prognosis. Therefore, we comprehensively investigated immune cell frequencies in matched peripheral blood, ascites, and tumor samples of 24 high-grade serous OC patients by flow cytometry and associated them with clinical parameters. Immune cell analysis demonstrated that the general immune cell infiltration was comparable between the three investigated compartments, with decreased proportions of CD8+ T cells in advanced stage OC. In addition, immune cell subsets varied significantly in their differentiation and phenotypic marker expression. In peripheral blood, classical monocytes, mature natural killer (NK) cells with cytotoxic potential (CD57+, CD16+, NKG2D+), and less differentiated T cells were more frequent. On the contrary, dendritic cells, and NKp46+ NK cells were prevalent in ascites. In OC tissues, high frequencies of immature neutrophils, CD16- NK cells, and effector memory T cells were found, although the intratumoral T cell frequency was significantly reduced compared to the two liquid samples. Additionally, T cell profiling showed high expression of one or multiple activating and inhibitory receptors in tumor samples. In particular, significant positive correlations of CD127+ CD8+ T cells among all three compartments were shown. Our results provide evidence that a higher proportion of peripheral CD127+ CD8+ T cells, which are memory T cells with low granzyme B production, was a prognostic biomarker for unfavorable progression-free survival of high-grade OC patients, independent of FIGO stage III/IV or residual tumor after surgery.

Keywords:  gynecologic cancer; immunological biomarker; immunophenotyping; liquid biopsy; local and peripheral immune system; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1607471