bims-tuinly 2025-08-31 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–08–31
seventeen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Efficacy and safety of one-time autologous tumor-infiltrating lymphocyte cell therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.
Functional tumor-reactive CD8 + T cells in pancreatic cancer.
Prognostic Value of Tumor Infiltrating Lymphocytes in Luminal B Breast Cancer Based on Multiphoton Microscopy.
Assessment of SF3B1 Expression as a Prognostic Marker for Neoadjuvant Chemotherapy Response in Stage III Triple-Negative Breast Cancer.
Six cycles of neoadjuvant chemotherapy followed by cytoreduction in high-grade serous ovarian cancer: prognostic implications of the chemotherapy response score, CA-125, and tumor-infiltrating lymphocytes.
Plasma exosomes from individuals with type 2 diabetes drive breast cancer aggression in patient-derived organoids.
Tumor microenvironment-based classification for predicting gastric cancer prognosis.
The significance of tumor microenvironment for immunotherapy in melanoma and non-melanoma skin cancer.
CDK4/6 inhibitors synergize with radiotherapy to prime the tumor microenvironment and enhance the antitumor effect of anti-PD-L1 immunotherapy in triple-negative breast cancer.
Tumor Microenvironmental Dynamics in Shaping Resistance to Therapeutic Interventions in Melanoma: A Narrative Review.
Heterogeneity and distribution characteristics of tertiary lymphoid structures predict prognostic outcome in esophageal squamous cell carcinoma.
Polyclonal expansion of functional tumor-reactive lymphocytes infiltrating glioblastoma for personalized cell therapy.
Aryl hydrocarbon receptor-ligand hexachlorobenzene promotes immunosuppression leading to mammary tumor growth and metastasis in a HER2-positive syngeneic mouse model.
Tumor Immune Response as a Biomarker for Metastasis-Free Survival of Breast Cancer and Immune Checkpoint Inhibition Therapy: A Retrospective Cohort Study.
Engineered T cells stimulate dendritic cell recruitment and antigen spreading for potent anti-tumor immunity.
Prediction of CD8+ T cell infiltration in the tumor microenvironment of HGSOC patients.
The transcription factor FOXA1 upregulates PYCR1-mediated autophagy to suppress antitumor immunity in lung adenocarcinoma.

J Immunother Cancer. 2025 Aug 24. pii: e011633. [Epub ahead of print]13(8):

Efficacy and safety of one-time autologous tumor-infiltrating lymphocyte cell therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.

Robert L Ferris, Rom S Leidner, Christine H Chung, Antonio Jimeno, Sylvia M Lee, Ammar Sukari, Jorge J Nieva, Juneko E Grilley-Olson, Rebecca Redman, Stuart J Wong, Victoria M Villaflor, Jamal Misleh, Friedrich Graf Finckenstein, Jeffrey Chou, Brian Gastman, Rana Fiaz, Melissa Catlett, Min Yi, Ezra E W Cohen.

   BACKGROUND: Recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) has a high recurrence rate after first-line immunotherapy or chemoimmunotherapy. The presence of a high density of tumor-infiltrating lymphocytes (TILs) in HNSCC tumors was shown to be associated with improved clinical outcomes. One-time autologous TIL cell therapy was evaluated in patients with recurrent and/or metastatic HNSCC.
METHODS: C-145-03 (NCT03083873) was a phase 2 study of TIL in patients with recurrent and/or metastatic HNSCC assigned to 1 of 4 treatment cohorts: cohort 1, non-cryopreserved TIL; cohort 2, cryopreserved lifileucel (22-day manufacturing); cohort 3, cryopreserved lifileucel (16-day manufacturing); cohort 4, cryopreserved LN-145-S1 programmed cell death protein-1 (PD-1) selected. Patients underwent tumor resection for TIL generation. After preparative non-myeloablative lymphodepletion, patients received a single infusion of TIL followed by interleukin-2 (IL-2) infusion(s). The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria for Solid Tumors (RECIST) V.1.1. Secondary endpoints were investigator-assessed duration of response (DOR), disease control rate (DCR), progression-free survival, overall survival, and incidence of treatment-emergent adverse events.
RESULTS: Overall, 53 patients received TIL: cohort 1 (n=8), cohort 2 (n=17), cohort 3 (n=16), cohort 4 (n=12). Median age was 57 years and most patients were males (87%; 46/53) with stage IV disease (98%; 52/53). Patients had a median of two prior lines of systemic therapy; 87% (46/53) of patients had prior anti-PD-1/programmed cell death ligand-1 therapy and 72% (38/53) had prior chemotherapy. The ORR was 11% (6/53) with six patients achieving partial response (cohort 1, n=3; cohort 2, n=1; cohort 4, n=2). At median follow-up of 17.9 months, the median DOR was 7.6 months. The DCR was 76% (40/53); 64% (34/53) of patients had stable disease. The safety profile was consistent with known toxicities associated with non-myeloablative lymphodepletion and IL-2 administration.
CONCLUSIONS: This study demonstrated the feasibility of consistently generating sufficient TIL from HNSCC tumors. Results from this study suggest TIL cell therapy may serve as a potential treatment option for patients with HNSCC and support further development, including TIL cell therapy combined with immune checkpoint inhibitors or other agents or with other TIL products.
TRIAL REGISTRATION NUMBER: NCT03083873.

Keywords:  Head and Neck Cancer; Immunotherapy; Tumor infiltrating lymphocyte - TIL

DOI:  https://doi.org/10.1136/jitc-2025-011633
J Exp Clin Cancer Res. 2025 Aug 25. 44(1): 253

Functional tumor-reactive CD8 + T cells in pancreatic cancer.

Hongwei Sun, Changying Shi, Guoqing Fang, Qiufang Guo, Zhengliang Du, Geer Chen, Yasong Wu, Zhe-Sheng Chen, Jian Hua, Yan Zhang, Zhiwen Shi.

   BACKGROUND: Traditional methods for detecting tumor-reactive (TR) CD8 + tumor-infiltrating lymphocytes (TILs) in pancreatic cancer usually focus on neo-antigenic epitopes, which is limited by the narrow range of antigenic epitopes, and the lengthy and complex identification processes, resulting in an incomplete understanding of the biological characteristics of TR CD8 + TILs.
METHODS: This study introduces a novel approach that integrates single-cell sequencing with deep learning (DL), which enables the identification of tumor-reactive CD8 + T cells without neoantigen screening. The T Cell Receptor Engineered T (TCR-T) cell tumor organoid killing model was employed to validate the functionality of DL-identified TR CD8 + T cells, while spatial transcriptomics was used to confirm receptor-ligand interactions involving TR CD8 + TILs.
RESULTS: Comprehensive analyses of TR CD8 + TILs revealed impaired mitochondrial respiratory chain-related pathways regulated by the transcription factor FOS. The TIGIT-NECTIN2 axis was identified as an important immune checkpoint molecule in the tumor microenvironment of pancreatic cancer. T cell receptor (TCR) repertoire analysis demonstrated that some TR CD8 + TILs possess multiple TCR αβ combinations. Furthermore, TCR-T targeting experiments using tumor organoids revealed that combinations of multiple distinct TR TCRs exhibit significantly superior tumor-killing capabilities compared to a single type TCR. Clinically, a higher proportion of TR CD8 + TILs was positively associated with improved responses to neoadjuvant immunotherapy and longer overall survival in pancreatic cancer patients.
CONCLUSION: This study represents a significant advancement in the understanding of TR TIL biology and provides a rapid and accurate method to identify TR CD8 TILs.

Keywords:  Deep learning; Pancreatic cancer; Single cell sequencing; Tumor-reactive CD8 + TILs

DOI:  https://doi.org/10.1186/s13046-025-03517-1
J Biophotonics. 2025 Aug 26. e202500281

Prognostic Value of Tumor Infiltrating Lymphocytes in Luminal B Breast Cancer Based on Multiphoton Microscopy.

Xi Chen, Deyong Kang, Zhonghua Han, Jianping Huang, Zhen Lu, Jiajia He, Zhijun Li, Yuxuan Luo, Xingfu Wang, Lianhuang Li, Xiahui Han, Jianxin Chen, Liqin Zheng, Junzhen Jiang.

  This study investigates the prognostic value of tumor-infiltrating lymphocytes (TILs) in luminal B breast cancer patients using multiphoton microscopy (MPM) and evaluates their association with 5-year disease-free survival (DFS). We obtained unlabeled MPM images from 213 patients, quantified the frequency of TILs, and assigned a TILs-score to each patient using ridge regression analysis. In addition, compared with single CLI-score model, the nomogram model, which integrated the TILs-score model with CLI-score model, further enhanced the predictive power for the luminal B subgroup. Specifically, the area under the curve (AUC) for 5-year DFS increased from 0.740 to 0.830 and hazard ratio (HR) increased from 5.31 to 7.24 in the training cohort; in the validation cohort, AUC increased from 0.716 to 0.822 and HR increased from 3.08 to 5.01. These findings suggest that the MPM-based TILs-score is a robust prognostic factor for luminal B breast cancer, potentially guiding more tailored treatment protocols.

Keywords:  breast cancer; luminal B subtype; multiphoton microscopy; prognosis; tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1002/jbio.202500281
Rep Biochem Mol Biol. 2025 Jan;13(4): 570-578

Assessment of SF3B1 Expression as a Prognostic Marker for Neoadjuvant Chemotherapy Response in Stage III Triple-Negative Breast Cancer.

Desak Made Wihandani, Putu Anda Tusta Adiputra, Gede Wikania Wira Wiguna, Putu Gede Septiawan Saputra, Made Violin Weda Yani, Ida Ayu Widya Anjani, Wayan Ardyan Sudartha Putra, Gede Putu Supadmanaba.

   Background: SF3B1 is a splicing factor that plays a crucial role in cancer progression and is commonly found in various types of solid cancers. However, the reports regarding the clinical implications of SF3B1 in terms of therapy response, survival, and its relationship with patients' clinicopathological features are still limited. This study aimed to assess SF3B1 expression for neoadjuvant chemotherapy response in stage III triple-negative breast cancer.
Methods: This case-control study was conducted at Prof. Dr. I.G.N.G. Ngoerah General Hospital from March to October 2021. Stage III TNBC breast cancer patients who received neoadjuvant chemotherapy were included. Variables assessed included SF3B1 expression, NAC response, and various histological and clinical parameters. Immunohistochemistry (IHC) for SF3B1 expression was performed using the avidin-biotin method. Data analysis involved univariate, bivariate (chi-square), and multivariate (logistic regression) methods using SPSS, with significance set at p ≤ 0.05.
Results: Analysis showed that high Ki-67, tumor-infiltrating lymphocytes (TILs), and SF3B1 status significantly increased the risk of chemoresistance in TNBC breast cancer (OR=6.4, 95%CI=1.20-34.19, p-value=0.017; OR=4.8, 95%CI=1.05-21.75, p-value=0.031; OR=13.5, 95%CI=1.56-116.24, p-value=0.008, respectively) No significant relationships were found with age, grading, or menopausal status. Multivariate analysis confirmed these variables independently influenced chemoresistance, with aOR=14.4, 95%CI=1.80-115.73 for Ki-67 (p-value=0.012), aOR=6.7, 95%CI=1.12-40.46 for TIL (p-value=0.037), and aOR=13.714, 95%CI=1.56-116.24 for SF3B1 (p-value=0.018).
Conclusions: High SF3B1 expression, alongside high Ki-67 and TIL levels, is potentially a prognostic marker for chemoresistance in stage III TNBC. These findings suggest that targeting SF3B1 could offer a novel therapeutic approach in TNBC patients.

Keywords:  Marker; Neoadjuvant chemotherapy; Prognosis; SF3B1; TNBC

DOI:  https://doi.org/10.61186/rbmb.13.4.570
Int J Gynecol Cancer. 2025 Jul 28. pii: S1048-891X(25)01147-8. [Epub ahead of print]35(10): 102027

Six cycles of neoadjuvant chemotherapy followed by cytoreduction in high-grade serous ovarian cancer: prognostic implications of the chemotherapy response score, CA-125, and tumor-infiltrating lymphocytes.

Andre Lopes, Marilia Albanezi Bertolazzi, Samantha Cabral Severino da Costa, Valesca Bizinoto, Rossana Veronica Mendoza Lopez, Maria Luiza Nogueira Dias Genta, Jesus Paula Carvalho, Filomena Marino Carvalho.

   OBJECTIVE: To evaluate the prognostic value of the chemotherapy response score, a histopathologic grading system for tumor regression following neoadjuvant chemotherapy, along with post-treatment serum CA-125 levels and tumor-infiltrating lymphocyte density, in patients with high-grade serous ovarian carcinoma treated with 6 cycles of neoadjuvant chemotherapy followed by surgery.
METHODS: This retrospective cohort study included patients with histologically confirmed high-grade serous ovarian carcinoma treated at a single institution between 2008 and 2021. All patients completed 6 cycles of carboplatin- and paclitaxel-based neoadjuvant chemotherapy. The chemotherapy response score was assessed in omental and adnexal specimens and categorized as 1, 2, or 3. Tumor-infiltrating lymphocyte density in pre- and post-treatment samples was classified as low (<10%) or high (≥10%). Associations among the chemotherapy response score, CA-125 levels, tumor-infiltrating lymphocytes, and survival outcomes-including overall survival and disease-free survival-were analyzed using Kaplan-Meier estimates and Cox proportional hazards models.
RESULTS: Of 294 patients screened, 110 met the inclusion criteria. In the omentum, 35.6% had a Chemotherapy Response Score of 3, with a median overall survival of 56.7 months (HR 0.34, 95% CI 0.19 to 0.61). In the adnexa, 43.8% had a score of 2, 41.7% had a score of 1, and 14.6% had a score of 3. Median overall survival for adnexal score 2 was 50.6 months, compared to 33.8 months for score 1. Post-treatment CA-125 levels ≤35 U/mL were associated with higher chemotherapy response score categories and improved survival (HR 0.45, 95% CI 0.28 to 0.73). Tumor-infiltrating lymphocyte density ≥10% was more frequent in adnexal score 2 cases (88.5%, p = .006), but tumor-infiltrating lymphocyte levels-both pre- and post-treatment-were not independently associated with overall survival or disease-free survival.
CONCLUSIONS: The chemotherapy response score and post-treatment CA-125 levels are independent prognostic indicators following 6 cycles of neoadjuvant chemotherapy. Tumor-infiltrating lymphocyte density showed site-specific patterns but lacked independent prognostic significance for survival outcomes.

Keywords:  CA-125; Chemotherapy Response Score; High-Grade Serous Ovarian Carcinoma; Tumor-Infiltrating Lymphocytes

DOI:  https://doi.org/10.1016/j.ijgc.2025.102027
Commun Biol. 2025 Aug 26. 8(1): 1276

Plasma exosomes from individuals with type 2 diabetes drive breast cancer aggression in patient-derived organoids.

Christina S Ennis, Michael Seen, Andrew Chen, Heejoo Kang, Adrian Ilinski, Kiana Mahdaviani, Naomi Y Ko, Stefano Monti, Gerald V Denis.

Women with obesity-driven type 2 diabetes (T2D) face worse breast cancer outcomes, yet metabolic status does not fully inform current standards of care. We previously identified plasma exosomes as key drivers of tumor progression; however, their effect on immune cells within the tumor microenvironment (TME) remains unclear. Using a novel patient-derived organoid (PDO) system that preserves native tumor-infiltrating lymphocytes (TILs), we show that T2D plasma exosomes induce a 13.6-fold expansion of immunosuppressive TILs relative to nondiabetic controls. This immune dysfunction may promote micrometastatic survival and resistance to checkpoint blockade, a known issue in T2D cancer patients. Tumor-intrinsic analysis revealed a 1.5-fold increase in intratumoral heterogeneity and 2.3-fold upregulation of aggressive signaling networks. These findings reveal how T2D-associated metabolic dysregulation alters tumor-immune crosstalk through previously underappreciated exosomal signaling, impairing antitumor immunity and accelerating progression. Understanding these dynamics could inform tailored therapies for this high-risk, underserved patient population.

DOI: https://doi.org/10.1038/s42003-025-08663-y
Comput Biol Med. 2025 Aug 22. pii: S0010-4825(25)01290-9. [Epub ahead of print]197(Pt A): 110938

Tumor microenvironment-based classification for predicting gastric cancer prognosis.

Yiyu Hong, Sang Ah Chi, Hye Seung Lee, Inwoo Hwang, So Young Kang, Soomin Ahn, Kyunga Kim, Ji Yeong An, Min Gew Choi, Jun Ho Lee, Jae Moon Bae, Tae Sung Sohn, Kyoung-Mee Kim.

   BACKGROUND: The tumor microenvironment (TME), consisting of tumor-associated stroma and tumor-infiltrating lymphocytes (TIL), is crucial for prognostic information in gastric cancer (GC). Despite its potential, routine clinical adoption remains limited.
METHODS: In a study of 320 GC patients, virtual staining and image processing were applied to hematoxylin & eosin-stained slides. This method quantified the tumor-stroma ratio (TSR) and TIL, leading to a TME-based prediction model (TMEPATH) using a scoring system derived from univariate Cox regression. Subgroups were categorized to predict GC patient survival, with genomic analysis linking TME-based prognostic models to specific genetic alterations.
RESULTS: TSR was categorized into TSR_low (n = 113) and TSR_high (n = 207) using a 0.76 cut-off, selected to maximize the concordance index for overall survival prediction. Two TIL subtypes were defined based on a 0.03 cut-off. TMEPATH, a composite biomarker integrating the TSR- and TIL-based subtypes, stratified patients into low-risk (91 patients, 28.4 %), medium-risk (167 patients, 52.2 %), and high-risk (62 patients, 19.4 %) groups, correlating with survival outcomes (hazard ratio [HR] 1.281; 95 % CI 0.957-1.714 for medium vs. low-risk, and HR 1.768; 95 % CI 1.242-2.517 for high vs. low-risk; log-rank P = 0.0061). These findings were validated in a separate cohort (n = 186) with significant clinical relevance (HR 1.389; 95 % CI 0.855-2.257 for medium vs. low-risk, and HR 2.435; 95 % CI 1.380-4.298 for high vs. low-risk; log-rank P = 0.0064). TSR, TIL, and TMEPATH were associated with microsatellite instability, tumor mutation burden, and CDH1 mutations.
CONCLUSION: The classification of GC into three TME subtypes using TSR and TIL provides a reliable prognostic tool for survival prediction.

Keywords:  Deep learning; Gastric cancer; Immune; Prediction; Risk; Stroma

DOI:  https://doi.org/10.1016/j.compbiomed.2025.110938
Immunol Med. 2025 Aug 25. 1-11

The significance of tumor microenvironment for immunotherapy in melanoma and non-melanoma skin cancer.

Taku Fujimura.

  Immune checkpoint inhibitors (ICIs), such as anti-PD-1 antibody, have significantly changed the treatment landscape not only for unresectable melanoma but also for non-melanoma skin cancers. In addition, anti-PD-1 antibody administration methods have evolved and are now used in both the neoadjuvant and adjuvant settings. As these treatment strategies have been evaluated, it has become clear that understanding the role of the tumor microenvironment (TME) is critical to the success of anti-PD-1 antibody-based immunotherapy. For example, racial differences in the efficacy of immunotherapy in melanoma are influenced not only by tumor-related factors such as tumor mutational burden and microsatellite instability, but also by components of the TME, including tumor-associated macrophages, cancer-associated fibroblasts, and tumor-infiltrating lymphocytes (TILs), all of which can affect the therapeutic outcome of ICIs. Furthermore, studies conducted during the development of neoadjuvant therapies have shown that tumor-reactive TILs are densely localized within primary tumors and are closely associated with both treatment efficacy and the occurrence of immune-related adverse events. In this review, we discuss the therapeutic efficacy of currently available anti-PD-1 antibody-based immunotherapies for skin cancer and examine the role of the TME in influencing these therapeutic outcomes.

Keywords:  Immune checkpoint inhibitors; anti-PD-1 antibody; combination therapy; tolerance; tumor microenvironment

DOI:  https://doi.org/10.1080/25785826.2025.2550795
J Biomed Sci. 2025 Aug 20. 32(1): 79

CDK4/6 inhibitors synergize with radiotherapy to prime the tumor microenvironment and enhance the antitumor effect of anti-PD-L1 immunotherapy in triple-negative breast cancer.

Wen-Chi Yang, Ming-Feng Wei, Ying-Chun Shen, Chiun-Sheng Huang, Sung-Hsin Kuo.

   BACKGROUND: Triple-negative breast cancer (TNBC) has the highest mortality rate among all breast cancer subtypes. Although immunotherapy shows promise, its efficacy varies. CDK4/6 inhibitors can radiosensitize and modulate the immune system, and high-dose radiotherapy (RT) can enhance the effects of immunotherapy. This study explored the combination of RT with CDK4/6 inhibitors to improve TNBC immunotherapy by modulating the tumor microenvironment.
METHODS: We assessed the radiosensitizing effects of abemaciclib (a CDK4/6 inhibitor) using clonogenic assays in three human TNBC cell lines (MDA-MB-231, MDA-MB-453, and MDA-MB-468) and two murine TNBC cell lines (4T1 and EMT6). The antitumor efficacy of the treatments (control, RT, abemaciclib, anti-PD-L1 antibody [aPD-L1], abemaciclib combined with aPD-L1, abemaciclib combined with RT, aPD-L1 combined with RT, and the triple combination of abemaciclib with aPD-L1 and RT) was evaluated in both 4T1 and EMT6 cell line-derived immunocompetent mouse models. Interferon-γ (IFN-γ) levels in mouse blood were monitored to gauge the immune response. Tumor-infiltrating lymphocytes (TILs) were analyzed using flow cytometry and immunohistochemical staining.
RESULTS: Clonogenic assays showed synergistic effects of RT and abemaciclib in all TNBC cell lines. RT increased PD-L1 expression, whereas abemaciclib did not alter PD-L1 expression. In the 4T1 and EMT6 mouse models, the triple combination treatment markedly inhibited tumor growth (P < 0.01). In the 4T1 mouse model, the triple combination group exhibited significantly greater circulating IFN-γ levels (P < 0.001) than the other groups. TIL analysis revealed a significant increase in CD4 + and CD8 + T cells and tumor-associated macrophages (P < 0.01) in the triple combination therapy group. Immunohistochemical staining confirmed increased infiltration of CD4 + T cells, CD8 + T cells, monocyte chemoattractant protein-1, CD80-, and iNOS- positive macrophages into the tumor microenvironment of this group, with a marked reduction in CD206-positive macrophages.
CONCLUSION: Combining CDK4/6 inhibitors with RT enhanced the antitumor effects of aPD-L1 immunotherapy against TNBC. This effect was correlated with increased IFN-γ secretion and recruitment of CD4 + and CD8 + T cells and M1 tumor-associated macrophages, leading to modulation of the tumor microenvironment.

Keywords:  CDK4/6 inhibitor; Immunotherapy; Radiotherapy

DOI:  https://doi.org/10.1186/s12929-025-01173-3
Pharmaceuticals (Basel). 2025 Jul 22. pii: 1082. [Epub ahead of print]18(8):

Tumor Microenvironmental Dynamics in Shaping Resistance to Therapeutic Interventions in Melanoma: A Narrative Review.

Laci M Turner, Hanna Terhaar, Victoria Jiminez, Bailey J Anderson, Emily Grant, Nabiha Yusuf.

  Background/Objectives: This review discusses the resistance mechanisms in the tumor microenvironment (TME) of malignant melanoma that disrupt the efficacy of immune checkpoint inhibitors (ICIs). In this review, we focus on the roles of immune cells, including tumor-infiltrating lymphocytes (TILs), macrophages, dendritic cells, and other signaling pathways. We explore the interplay between innate and adaptive immunity in the TME and tumor intrinsic resistance mechanisms, such as β-catenin, which has future implications for the usage of ICIs in patients with therapy-resistant tumors. Methods: A total of 1052 studies were extracted from the PubMed database searching for keywords and phrases that included [melanoma AND immune checkpoint inhibitor resistance]. After a title/abstract and full-text review, 101 studies were identified that fit the inclusion/exclusion criteria. Results: Cancer-associated fibroblasts (CAFs), M2 macrophages, and myeloid-derived suppressor cells (MDSCs) are significant in remodeling the TME to promote melanoma growth. Melanoma resistance to ICIs is complex and involves TME alterations, tumor intrinsic factors, and immune evasion. Key components of resistance include reduced CD8+ T cell infiltration, decreased host immune response, and immunosuppressive cytokines. Conclusions: Predictive biomarkers and specific models are the future of individualized melanoma management and show great promise in their approach to targeted therapy production. Tumor profiling can be utilized to help predict the efficacy of ICIs, and specific biomarkers predicting therapy responses are instrumental in moving towards personalized and more efficacious medicine. As more melanoma resistance emerges, alternative and combinatorial therapy based on knowledge of existing resistance mechanisms will be needed.

Keywords:  CTLA-4; PD-L1; immune checkpoint inhibitors; melanoma; resistance; tumor microenvironments

DOI:  https://doi.org/10.3390/ph18081082
Front Immunol. 2025 ;16 1606499

Heterogeneity and distribution characteristics of tertiary lymphoid structures predict prognostic outcome in esophageal squamous cell carcinoma.

Chengjuan Zhang, Ruihua Bai, Yanping Hu, Tao Wang, Bin Ma, Junxia Zhang, Jing Yuan, Xiance Tang, He Zhang, Tingjie Wang, Yuxi Chang, Qingxin Xia, Bing Wei.

   Objective: Tertiary Lymphoid Structures (TLSs) are ectopic lymphoid aggregates that form within the tumor microenvironment (TME) and are increasingly recognized as potential prognostic biomarkers in various cancers. However, the spatial heterogeneity and prognostic value of TLSs in esophageal squamous cell carcinoma (ESCC) remain poorly defined. This study aimed to characterize the spatial distribution patterns of TLSs and tumor-infiltrating lymphocytes (TILs), and to establish a refined prognostic model for ESCC patients in both surgery-only and neoadjuvant therapy cohorts.
Methods: The TLSs were quantified through microscopic evaluation and digital slide analysis and correlated with prognosis by Cox regression and Kaplan-Meier analyses. The heterogeneity and clinical prognostic value of TLSs were explored by analyzing their distribution, density, and maximum diameter in different regions of ESCC patients.
Results: TLSs showed spatial distribution heterogeneity in the tumor area, adjacent area, and marginal area, with consistent differences observed across different paraffin blocks. The distribution of iTIL and sTIL also exhibited certain spatial heterogeneity. In the surgical cohort (n = 117), the median Overall Survival (OS) and Disease-Free Survival (DFS) were 33 months and 15 months, respectively. Univariate analyses showed that TLS presence in tumor (TG), TLS-rich regions (TR), TLS ratio in normal regions (NR), tumor-stroma ratio (TSR), and both iTIL and sTIL levels were significantly associated with OS (p < 0.05). Multivariate analysis confirmed N stage, TG, TR, TLS abundance in adjacent regions (NA), and TLS density in tumor (NT), along with TSR, iTIL, and sTIL, as independent predictors of prognosis (p < 0.05). High TLS presence in tumor regions (TG-high) was associated with significantly improved OS (log-rank p = 0.026).
Conclusion: This study demonstrates that TLSs and TILs in ESCC are not only prognostically relevant but also spatially heterogeneous. The refined spatial immune profiling across multiple tumor regions improves prognostic stratification and may inform personalized treatment planning in ESCC.

Keywords:  N stage; TG; TR; esophageal cancer; heterogeneity; nr; prognosis their heterogeneity in esophageal squamous univariate analysis revealed that T stage; tertiary lymphoid structures

DOI:  https://doi.org/10.3389/fimmu.2025.1606499
Nat Commun. 2025 Aug 25. 16(1): 7279

Polyclonal expansion of functional tumor-reactive lymphocytes infiltrating glioblastoma for personalized cell therapy.

Martina Maffezzini, Silvia Musio, Natalia Di Ianni, Agnese Rumolo, Monica Patanè, Andrea Galluzzo, Irene Sambruni, Arianna Berlendis, Domenico Aquino, Giacomo Baso, Manuela Zingarelli, Manuel Facciolla, Luisa Maddaloni, Rossella Valentino, Rosina Paterra, Fabio Agistri, Mariangela Farinotti, Luca Mattei, Paola Coluccia, Francesco Acerbi, Francesco DiMeco, Bianca Pollo, Antonio Silvani, Marica Eoli, Catia Traversari, Daniela Montagna, Serena Pellegatta.

Tumor-infiltrating lymphocyte (TIL)-therapy has received FDA approval for the treatment of advanced melanoma and shows potential for broader applications in solid tumors, including glioblastoma. In this study, tumor-reactive TILs (tr-TILs) are isolated and enriched for CD137 expression from cavitron ultrasonic aspirator (CUSA) emulsions of 161 adult patients diagnosed with diffuse gliomas. Tr-TILs are successfully expanded in 87 out of the 161 patients, reflecting an expansion rate of 54%. Notably, the presence of IDH1 mutation and the cumulative dose of steroids are identified as significant negative predictors of expansion efficacy. The expanded tr-TILs exhibit distinct phenotypic and molecular dysfunctional features yet show upregulated expression of progenitor/memory-like markers and polyclonal T-cell receptors. Importantly, these tr-TILs demonstrate specific antitumor reactivity against autologous tumor cells in both in vitro and in vivo xenograft models. These findings provide a compelling background for a personalized immunotherapeutic approach while tackling one of the most significant challenges in oncology.

DOI: https://doi.org/10.1038/s41467-025-62263-2
Environ Toxicol Pharmacol. 2025 Sep;pii: S1382-6689(25)00171-1. [Epub ahead of print]118 104796

Aryl hydrocarbon receptor-ligand hexachlorobenzene promotes immunosuppression leading to mammary tumor growth and metastasis in a HER2-positive syngeneic mouse model.

Lorena V Zárate, Jorge A Peña Agudelo, Noelia V Miret, Alejandro J Nicola Candia, Melanie Pérez Kϋper, Carolina A Pontillo, Florencia A Chiappini, Marianela Candolfi, Andrea S Randi.

  Pesticide exposure has been established as a risk factor for breast cancer. Hexachlorobenzene (HCB) is an aryl hydrocarbon receptor (AhR) ligand. Mice bearing LM3 HER2(+) breast tumors were exposed to HCB (35 and 15 days). Tumor growth and lung metastases were evaluated, and key molecules were analyzed by western blot, immunofluorescence and RT-qPCR. Splenic and tumor infiltrating lymphocytes (TILs) were quantified by flow cytometry. Results showed that HCB (35 days) accelerates tumor growth and promotes lung metastases development. HCB upregulates AhR, CYP1A2, IDO1, COX-2 and VEGF expression. The pesticide reduces ERβ and increases GPER levels. Exposure to HCB decreases the content of CD8 + and regulatory T cells in the spleen and antigen-presenting cells in the tumor, without changes in TILs. HCB (15 days) suppresses CD4 + and CD8 + infiltration in tumors. Our findings indicate that HCB facilitates tumor progression in HER2(+) breast cancer, involving the dysregulation of ERs and pro-angiogenic factors. Likewise, AhR overexpression could be modulating the anti-tumor immune response, inducing immunosuppression.

Keywords:  Estrogen receptors; HER2(+) breast cancer; Immunosuppression; Lung metastasis; Pesticide; Pro-angiogenic factors; Tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.etap.2025.104796
Breast Cancer (Auckl). 2025 ;19 11782234251363665

Tumor Immune Response as a Biomarker for Metastasis-Free Survival of Breast Cancer and Immune Checkpoint Inhibition Therapy: A Retrospective Cohort Study.

Chung-Wu Lin, Kai-Ming Chang, Wen-Hui Ku, Kuo-Jang Kao.

   Background: Breast cancers (BRCs) can be classified into 6 molecular subtypes based on gene expression profiles. Previous research suggests that tumor-infiltrating lymphocytes are associated with metastasis-free survival (MFS) in triple-negative and HER2-overexpressing BRC.
Objectives: Our study aims to investigate further how the immune response (IR) may impact MFS in different molecular subtypes of BRC.
Design: A single hospital-based retrospective cohort study.
Methods: A training series of 327 BRCs was used to identify 297 IR transcripts that were correlated with the T cell-associated CD3D transcript or the B cell-associated CD19 transcript. Using these IR transcripts, each of the 6 molecular subtypes was hierarchically clustered into high and low immune responders. An IR score based on the average of the 297 IR transcripts was determined for each BRC. Correlations between the IR score and 3 signatures for IR or response to immune checkpoint inhibition therapy (ICIT) were investigated. A series of 884 BRCs from public datasets was used for confirmation, and the other independent series of 988 BRCs was used for validation.
Results: For subtype I, high immune responders had a statistically significantly better MFS than low immune responders in all the training, confirmation, and validation series by Kaplan-Meier survival analysis (P = .0039, .049, .039, log-rank test). The same trend was observed for subtype II (P = .16, .052, .015) and subtype IV (P = .0078, .0002, .12). Our IR scores were linearly correlated with the Teschendorff, the T-effector and IFNg, and the T-cell inflamed signatures for IR or ICIT. The IR scores were also linearly correlated with the expression of 6 different immune checkpoint genes.
Conclusions: Tumor IR is a biomarker for MFS for BRCs of I, II, and IV subtypes. Our study supports the potential use of the IR score for identifying patients responsive to ICIT.

Keywords:  Tumor immune response; breast cancer; chemotherapy; immune checkpoint inhibition therapy; metastasis-free survival; molecular subtypes

DOI:  https://doi.org/10.1177/11782234251363665
Cell Rep Med. 2025 Aug 20. pii: S2666-3791(25)00380-5. [Epub ahead of print] 102307

Engineered T cells stimulate dendritic cell recruitment and antigen spreading for potent anti-tumor immunity.

Zhen Xiao, Jiajia Wang, Shidian He, Lin Wang, Jingxing Yang, Wenhui Li, Kaili Ma, Yabo Zhou, Xiaowei Liu, Shiyou Wang, Yu Yang, Minmin Ge, An Gao, Kun Tang, Jing Huang, Chen Wang, Liyuan Zhang, Hai-Xi Sun, Lianjun Zhang.

  Current T cell-based immunotherapeutic strategies show limited success in treating solid tumors due to insufficient dendritic cell (DC) activity, particularly cross-presenting conventional type 1 dendritic cells (cDC1s). DC scarcity and dysfunction hinder T cell expansion and differentiation, greatly limiting anti-tumor responses. In this study, we propose a T cell engineering strategy to enhance interaction with XCR1+ cDC1s. Adoptively transferred T cells engineered to secrete Flt3L and XCL1 (FX) promote DC trafficking and maturation and improve DC-T cell interaction, while maintaining a pool of TCF1+SlamF6+ stem-like T cells. Importantly, FX-engineered T cells trigger robust antigen spreading and potent endogenous polyclonal T cell response, enabling the recognition and elimination of tumors with heterogeneous antigens and preventing immune escape. The therapeutic efficacy of FX-armed chimeric antigen receptor (CAR)-T cells is further validated in the Flt3KO&hFLT3LG humanized mouse model. This strategy offers a promising avenue for enhancing DC-T cell interactions, paving the way for more effective immunotherapy against solid tumors.

Keywords:  CAR-T cell; antigen spreading; dendritic cell; endogenous T cell; humanized mouse model; immunotherapy; stem-like T cells

DOI:  https://doi.org/10.1016/j.xcrm.2025.102307
Sci Rep. 2025 Aug 20. 15(1): 30518

Prediction of CD8+ T cell infiltration in the tumor microenvironment of HGSOC patients.

Jia Mai, Ling Yang, YuXin Chen, XiaoXu Zeng, HongJian Xie, XiaoJuan Liu.

  The tumor microenvironment (TME), particularly CD8+ T cell infiltration, critically influences high-grade serous ovarian cancer (HGSOC) progression and treatment response. The development and management of cancer depend heavily on CD8+ T cells. Identifying non-invasive predictors of TME immune status is crucial. We investigated whether clinicopathologic characteristics and peripheral blood parameters could predict CD8+ T infiltration in TME of HGSOC. Two independent cohort were analyzed: (1) A multicenter tissue microarray (TMA) cohort of 105 epithelial ovarian cancer cases revealed that high CD8+ T cell density in tumor parenchyma, stroma, or whole tissue was significantly associated with good prognosis. (2) A retrospective cohort of 95 HGSOC patients from West China Second University Hospital (2016-2020) demonstrated that peripheral blood lymphocytes, globulin (GLB), lactate dehydrogenase (LDH), and low-density lipoprotein (LDL) correlated with CD8+ T cell infiltration in TME. These findings support non-invasive blood markers as predictors of tumor immune status and highlight chemotherapy's role in enhancing CD8+ T cell recruitment.

Keywords:  CD8+ T cells; High-grade serous ovarian cancer; Peripheral blood parameters; Prognosis; Spatial distribution; Tumor microenvironment

DOI:  https://doi.org/10.1038/s41598-025-14720-7
Cancer Immunol Immunother. 2025 Aug 23. 74(9): 290

The transcription factor FOXA1 upregulates PYCR1-mediated autophagy to suppress antitumor immunity in lung adenocarcinoma.

Kui Liu, Xiaoyan Yang, Xuemei Tang, Bo Tang.

   BACKGROUND: Immunotherapy has emerged as an effective treatment for lung adenocarcinoma (LUAD) in recent years. However, the ability of cancer cells to suppress antitumor immune responses through multiple mechanisms has become one of the major challenges for therapy. PYCR1 can reinforce the proliferation of LUAD cells, but the function of PYCR1 in LUAD against the tumor immune response has not been fully elucidated.
METHODS: The clinical significance of PYCR1 in LUAD and the relationship between PYCR1 expression and CD8+ T cell infiltration were examined by bioinformatics analysis. The expression of PYCR1 and CD8 in LUAD clinical samples was analyzed by immunohistochemistry. The expression of PYCR1 in the LUAD cell model was detected by qPCR. Flow cytometry, lactate dehydrogenase kit, Calcein-AM/PI staining, and Transwell were employed to analyze the effect of PYCR1 on CD8+ T cell function. Western blot and immunofluorescence were utilized to probe into the effect of PYCR1 on autophagy. The interaction between PYCR1 and FOXA1 was evaluated by dual-luciferase assay and ChIP assay. Finally, in vitro and in vivo rescue experiments were conducted to verify the role of the FOXA1/PSYR1 axis in the immune regulation of LUAD.
RESULTS: PYCR1 was upregulated in LUAD and was linked with the dismal prognosis of patients. Knockdown of PYCR1 in LUAD remarkably enhanced the activity of peripheral CD8+ T cells and facilitated the death of LUAD cells. In addition, overexpression of PYCR1 activated autophagy in cancer cells and dampened the anti-tumor immune response of CD8+ T cells. FOXA1 was an upstream transcriptional activator of PYCR1. Knockdown of FOXA1 potentiated the killing ability of CD8+ T cells on LUAD cells by repressing autophagy, while overexpression of PYCR1 reversed the effect of FOXA1 knockdown, which was verified in mouse experiments.
CONCLUSION: FOXA1 upregulates PYCR1 expression, activates autophagy in LUAD cells, and dampens CD8+ T cell antitumor immune response. Targeting FOXA1/PYCR1 may be a potential approach to improve LUAD immunotherapy.

Keywords:  Autophagy; CD8+ T cells; FOXA1; Lung adenocarcinoma; PYCR1

DOI:  https://doi.org/10.1007/s00262-025-04144-7