bims-tuinly 2025-07-13 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–07–13
nine papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Research progress of adoptive tumor infiltrating lymphocyte therapy for cervical cancer.
Prognostic value of tumor-infiltrating lymphocytes in irradiated node-positive breast cancer patients.
Tumor-Infiltrating Lymphocytes in Breast and Female Genital Tract Cancers: Overlooked Potential and Unexplored Frontiers.
An SNP-dependent cancer-testis antigenic epitope serves as a promising immunotherapeutic target for cancer.
Going With the Flow: Circulating Tumor-Reactive Lymphocytes Stream Into Cancer Therapy.
Lifileucel Therapy for Metastatic Melanoma: Advancements in Tumor-infiltrating Lymphocyte-based Immunotherapy.
Nomograms for stratified prognosis prediction of gastric cancer by integrating programmed death ligand 1 and tumor-infiltrating immune cells including CD4+/CD8+ TILs and CD163+ TAMs.
Selective expansion of TCF7-expressing tumor-reactive T cell subpopulations during ovarian tumor-infiltrating T cell production ex vivo.
Revealing the significance of tissue-resident memory T cells in lung adenocarcinoma through bioinformatic analysis and experimental validation.

Int J Gynaecol Obstet. 2025 Jul 10.

Research progress of adoptive tumor infiltrating lymphocyte therapy for cervical cancer.

Juncheng Zhang, Yafi Wang, Hongfang Li.

  Cervical cancer ranks as the fourth leading cause of cancer-related mortality among women globally, posing a significant threat to women's health. Immunotherapy has emerged as the fourth line of treatment for cervical cancer, following surgery, chemotherapy, and radiotherapy. It is particularly effective for recurrent and/or metastatic cervical cancer, yielding favorable clinical outcomes. Common immunotherapeutic approaches include immune checkpoint inhibitors, adoptive cell therapy, and cervical cancer vaccines. Among these, adoptive cell immunotherapy (ACT) represents an innovative and promising modality that has transformed the field of cancer immunotherapy in recent years. This review will specifically focus on tumor-infiltrating lymphocytes (TILs), examining the principles, limitations, improvement strategies, challenges, and future prospects of TIL-based treatment for cervical cancer. Collectively, these approaches offer a novel theoretical foundation and translational research direction for cervical cancer immunotherapy centered on TIL therapy.

Keywords:  adoptive tumor infiltrating lymphocyte therapy; cervical cancer; immune escape; immune microenvironment; immunotherapy

DOI:  https://doi.org/10.1002/ijgo.70360
Breast. 2025 Jun 30. pii: S0960-9776(25)00542-9. [Epub ahead of print]83 104525

Prognostic value of tumor-infiltrating lymphocytes in irradiated node-positive breast cancer patients.

Demet Özcan, Anders Winther Mølby Nielsen, Jan Alsner, Lise Bech Jellesmark Thorsen, Jens Overgaard, Birgitte Vrou Offersen, Trine Tramm.

   INTRODUCTION: Radiotherapy significantly reduces locoregional recurrence (LRR) and improves survival. Yet, reliable biomarkers predicting radiotherapy response are not well-defined. Tumor-infiltrating lymphocytes (TILs) have emerged as a promising prognostic and predictive marker, but their role in irradiated patients remains underexplored.
METHODS: This case-cohort study included 1461 node-positive, irradiated breast cancer patients from the Danish Breast Cancer Group (DBCG) internal mammary node (IMN)2 study. IMN irradiation (IMNI) was allocated by tumor laterality. TILs were assessed in treatment-naïve primary tumors and dichotomized using a 30 % cut-off. Endpoints included overall mortality (OM), breast cancer-specific mortality (BCM), distant recurrence (DR), and LRR. Flexible parametric survival models estimated adjusted hazard ratios (HRs).
RESULTS: TILs were evaluated in 1353 patients; 20 % had high TILs. Low TILs were associated with higher OM (HR 0.53, 95 % CI: 0.36-0.77), BCM (HR 0.45, CI: 0.29-0.71) and DR (HR 0.40, CI: 0.26-0.62), but not LRR (HR 0.82, CI: 0.31-2.17). These associations were strongest in estrogen receptor-negative (ER-) tumors. ER-/low TILs were associated with increased OM (HR 0.31, CI: 0.18-0.56) compared to ER-/high TILs, whereas TILs were not prognostic in ER+ tumors (HR 0.86, CI: 0.56-1.32). A significant survival benefit after IMNI was observed in patients with low TILs tumors (HR 0.64, CI: 0.48-0.85), but TILs did not predict IMNI-benefit.
CONCLUSION: TILs in the pre-immunotherapy setting were not predictive of IMNI-benefit but prognostic for post-radiotherapy outcomes in node-positive patients. The effect was dependent on ER status, as patients with ER-/low TILs tumors had poorer survival with a trend toward increased DR-risk.

Keywords:  Breast cancer; Estrogen receptor; Radiotherapy; Recurrence; Survival; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.breast.2025.104525
Cancer Med. 2025 Jul;14(13): e71023

Tumor-Infiltrating Lymphocytes in Breast and Female Genital Tract Cancers: Overlooked Potential and Unexplored Frontiers.

Kristijan Skok, Umberto Maccio, Spencer D Martin, Konstantin Bräutigam.

   BACKGROUND: The growing success of cancer immunotherapies has led to significant advances in oncology. However, despite these promising developments, cancer-related mortality remains high for common cancer types such as breast and lower female genital tract cancers.
METHOD: Here, we synthesize recent findings on the prognostic relevance of tumor-infiltrating lymphocytes (TILs) in breast, endometrial, tubo-ovarian, and vulvar cancer. Our analysis covers the relationship between TIL counts and density, immune cell subtype combinations, immunotherapy approaches, and patient outcomes.
RESULTS: High TIL infiltration, especially CD8+ T-cells, generally correlates with improved outcomes such as in endometrial cancer (especially the POLE-ultramutated subgroup), invasive breast cancer, and ovarian epithelial tumors. However, in ductal carcinoma in situ (DCIS) of the breast, elevated TIL counts are linked to a worse prognosis. Ethnicity, the tumor microenvironment (TME), and molecular profiles further complicate the prognostic utility of TILs.
CONCLUSIONS: TIL-based therapies have shown potential in personalized immunotherapy, particularly in recurrent, refractory ovarian cancer. Limited research on rarer gynecologic tumors hinders broader clinical applications.

Keywords:  breast cancer; endometrial cancer; fallopian tube; immunotherapy; ovarian cancer; review; tumor microenvironment (TME); tumor‐infiltrating lymphocytes (TILs); vulvar cancer

DOI:  https://doi.org/10.1002/cam4.71023
Oncoimmunology. 2025 Dec;14(1): 2528110

An SNP-dependent cancer-testis antigenic epitope serves as a promising immunotherapeutic target for cancer.

Kenji Murata, Tomoyuki Minowa, Tomohide Tsukahara, Taku Yoshida, Akiko Minami, Munehide Nakatsugawa, Yuka Mizue, Aiko Murai, Serina Tokita, Kenta Sasaki, Hisashi Uhara, Terufumi Kubo, Takayuki Kanaseki, Toshihiko Torigoe, Yoshihiko Hirohashi.

  T cells recognize peptides presented by human leukocyte antigen molecules on the cell surface, enabling the immune surveillance of pathological conditions such as cancer. Cancer-testis (CT) antigens are promising targets for cancer immunotherapy because of their restricted expression in normal tissues. In this study, we performed antigen screening of T cell receptors isolated from tumor-infiltrating lymphocytes (TILs) in acral melanoma, using cDNA expression cloning and identified a novel CT antigenic epitope encoded by MAGE-A6 with a single nucleotide polymorphism (SNP). This SNP conferred immunogenicity to the epitope, eliciting a robust immune response against tumor cells. While antigen identification has increasingly relied on reverse immunology approaches using reference sequences that do not contain SNPs, forward immunology approaches, such as cDNA expression cloning, directly identify antigens recognized by T cells exhibiting immune responses, enabling the detection of SNP-derived epitopes. Furthermore, in hot tumors such as acral melanoma that are characterized by a low tumor mutational burden, but high TIL infiltration, TILs predominantly respond to shared antigens with high immunogenicity. These findings underscore the utility of forward immunology in antigen discovery and highlight the potential of SNP-dependent tumor antigens in cancer immunotherapy.

Keywords:  Antigenic epitope; cDNA expression cloning; cancer-testis antigen; single nucleotide polymorphism; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1080/2162402X.2025.2528110
Clin Cancer Res. 2025 Jul 09.

Going With the Flow: Circulating Tumor-Reactive Lymphocytes Stream Into Cancer Therapy.

Rubén Alvarez-Rodríguez, Aleksandra Vuchkovska, Zongjie Wang, Cecile Chartier, Kristen Hege, Michael Kalos, Shana O Kelley.

Adoptive cell therapy (ACT), best exemplified to date by chimeric antigen receptor T-cell, engineered T‑cell receptor, and tumor-infiltrating lymphocyte (TIL) therapy, has emerged as a transformative approach in cancer immunotherapy. The broad application of ACT in solid tumors, however, has been limited due to several challenges, such as tumor-antigen heterogeneity, the suppressive tumor microenvironment, and T-cell exhaustion. TIL therapy harvests and expands tumor‑reactive T cells from excised tumors for reinfusion, now a clinical reality, despite complex manufacturing logistics. Circulating tumor-reactive lymphocytes (cTRLs) are naturally occurring T cells with antitumor reactivity that are found at low levels in the peripheral blood (PB) of patients with cancer. cTRLs are among a group of T cells that possesses unique phenotypic characteristics, allowing them to circulate between the bloodstream and tumor sites, including distant metastases, to provide systemic and local immune surveillance. Preclinical studies have demonstrated that cTRLs possess potent antitumor activity in vitro and in vivo. When compared with corresponding TILs, cTRLs show less exhaustion, enhanced cell fitness, and a greater concentration and diversity of tumor-specific T-cell clonotypes, suggesting that cTRLs may be well-suited for ACT. While cTRLs are typically rare cells in the PB, recent advances in cTRL detection and purification methods now enable the efficient isolation and scalable production of these cells for therapeutic applications. In this review, we highlight the biological characteristics of cTRLs, their role in cancer surveillance and therapy, and the preclinical and clinical evidence showcasing their potential for development as a therapeutic option for patients with cancer.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-0882
Anticancer Agents Med Chem. 2025 Jul 04.

Lifileucel Therapy for Metastatic Melanoma: Advancements in Tumor-infiltrating Lymphocyte-based Immunotherapy.

Issac V Cherian, Md Mustahidul Islam, Mamta Bishnoi, Sakshi Priya, Balak Das Kurmi, Sourabh Koshey, Preeti Patel.

  Metastatic melanoma is an aggressive malignancy with limited treatment options at advanced stages. Lifileucel, an FDA-approved autologous Tumor-Infiltrating Lymphocyte (TIL) therapy, marks a major advancement in immunotherapy, particularly for patients who fail conventional treatments like immune checkpoint inhibitors and targeted therapies. The mechanism of lifileucel involves the ex vivo expansion of patient-derived TILs to boost immune responses against melanoma cells. These expanded TILs are re-infused into patients, enhancing tumor-specific cytotoxicity and modulating the tumor microenvironment for sustained immune activation. Clinical trials have demonstrated its efficacy, with the overall response rate (ORR) reaching up to 36% in heavily pretreated populations, offering durable responses and improved progression-free survival compared to traditional therapies. The personalized approach of lifileucel, leveraging the patient's own T-cell repertoire, highlights its potential for precision oncology by targeting individual tumor profiles. Its integration with combination therapies, particularly immune checkpoint inhibitors, shows promising synergistic effects, broadening its clinical applicability. In addition to clinical success, the role of lifileucel in influencing the melanogenesis pathway offers insights into optimizing therapeutic strategies for melanoma. Ongoing research focuses on enhancing TIL functionality, overcoming challenges like tumor-induced immune suppression, and extending the applicability of lifileucel to other solid tumors. This breakthrough therapy not only addresses a critical unmet need in melanoma treatment but also represents a paradigm shift toward personalized medicine in oncology. Lifileucel underscores the potential of TILbased approaches to revolutionize cancer care, setting the stage for future advancements in immunotherapy.

Keywords:  Metastatic melanoma; lifileucel; melanogenesis pathway.; personalized medicine; tumor microenvironment; tumor-infiltrating lymphocyte therapy

DOI:  https://doi.org/10.2174/0118715206380598250622182719
Front Oncol. 2025 ;15 1530054

Nomograms for stratified prognosis prediction of gastric cancer by integrating programmed death ligand 1 and tumor-infiltrating immune cells including CD4+/CD8+ TILs and CD163+ TAMs.

Xiumin Qi, Yixuan Guo, Yan Xiao, Xiang Pan, Fangming Chen, Xu Zhang.

   Purpose: To develop nomograms for predicting disease-free survival (DFS) and overall survival (OS) of gastric cancer (GC) by integrating programmed death ligand 1 (PD-L1) and CD4+/CD8+ tumor-infiltrating lymphocytes (TILs) and CD163+ tumor-associated macrophages (TAMs).
Materials and methods: Immunohistochemistry for PD-L1, CD4+/CD8+ TILs and CD163+TAMs was performed on 126 surgically-resected GC specimens between January 2016 and May 2018. Subsequently, the expression of PD-L1 and these tumor-infiltrating immune cells(TIICs), in combination with multiple clinicopathologic features, was used to formulate nomograms for predicting DFS or OS based on the results of multivariate Cox regression analysis. The performance of the nomograms for DFS or OS was verified in the 10-fold cross-validation of the study cohort and measured by Harrell's concordance-index (C-index).
Results: After multivariable Cox regression analyses, high PD-L1 expression (hazard ratio[HR]=2.17, 95% confidence interval [CI] 1.37-3.43), low CD8+ TILs density(HR=0.35, 95% CI 0.15-0.81), high CD163+ macrophages density (HR=1.84, 95% CI 1.17-2.89), TNM stage (stage III vs stage I+II, HR=1.37, 95% CI 1.06-2.23) and microsatellite instability-high(MSI-H) ( MSI-H VS microsatellite stability (MSS), HR=0.41, 95% CI 0.20-0.83) were found to be independent risk factors for DFS. Similarly, high PD-L1 expression (HR=2.64, 95% CI 1.61-4.34), high CD4+ TILs density (HR=1.98, 95% CI 1.21-3.24), low CD8+ TILs density (HR=0.23 95% CI 0.07-0.73), high CD163+ TAMs density (HR=2.31, 95% CI 1.43-3.74), MSI-H (MSI-H VS MSS, HR=0.26, 95% CI 0.12-0.60) and TNM stage (stage III vs stage I +II, HR=1.61, 95% CI 1.01-2.56) were independently associated with OS. These actors were then selected to establish nomograms for DFS and OS individually. The established nomogram for DFS yielded a corrected C-index of 0.679 by 10- fold cross-validation. Similarly, the established nomogram for OS yielded a corrected C-index of 0.755.These results suggest that PD-L1 and high density of CD4+ TILsas well as CD163+ TAMs are risk factors for poor prognosis in GC patients.On the contrary, MSI-H and high density of CD8+ TILsare associated with good prognosis in GC patients.
Conclusions: The developed prognostic nomograms for GC integrating PD-L1 and CD4+/CD8+ TILs as well as CD163+TAMs offer a more personalized and precise prediction of DFS and OS for patients, which can help to improve prognostic stratification.

Keywords:  gastric cancer; nomogram; prognosis; programmed death-ligand 1; tumor-associated macrophages; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3389/fonc.2025.1530054
Sci China Life Sci. 2025 Jul 08.

Selective expansion of TCF7-expressing tumor-reactive T cell subpopulations during ovarian tumor-infiltrating T cell production ex vivo.

Dingfeng Liu, Ting Zhang, Qinli Sun, Dongli Cai, Yanan Lou, Genyu Wang, Bowen Xie, Yicheng Zhu, Chong Wang, Zhouping Lu, Chenfei Liu, Yuan Li, Xi Zhang, Tianhui He, Jing Hao, Xinyi Guo, Jiaming Li, Xiaowei Xi, Ling Ni, Hongyan Guo, Jing Ge, Liping Jin, Chen Dong.

  Tumor-infiltrating lymphocyte (TIL) therapy was recently approved for melanoma patients; however, the dynamic changes in T cell subpopulations during TIL production remain poorly understood. Here, we analyzed epithelial ovarian cancer samples at various stages of ex vivo TIL culture using paired single-cell RNA and TCR sequencing. We also assessed the expansion potential and tumor reactivity of the identified TIL subpopulations. Single-cell transcriptomic analysis revealed that CD8+ TILs exhibited reduced cellular diversity following ex vivo expansion, selectively expanding stem-like TCF7+ precursors of exhausted T cells (Tpex) and effector-like tissue-resident memory (Trm) cells. TCR clonotype analysis showed that Tpex cells accumulated through self-renewal, while Trm cells primarily originated from TCF7+GZMK+ early effector memory cells in tumors. Additionally, TCR tracing identified preferential activation and reprogramming of CD4+ T follicular helper (Tfh)-like cells, especially TCF7+ ones. All three TCF7+ subpopulations showed robust expansion potential and tumor reactivity in vitro. Notably, CCR7+CD200+ T cells, enriched for TCF-1+CD8+ Tpex and CD4+ Tfh-like cells in the tumor microenvironment, exhibited self-renewal during in vitro expansion and demonstrated tumor reactivity both in vivo and in vitro. These findings highlight the selective expansion of tumor-reactive TCF7+ T cells during TIL culture and suggest that CCR7 and CD200 serve as important surface markers for generating stem-like, tumor-reactive cells, potentially improving TIL therapy in cancers.

Keywords:  adoptive cell therapy; expansion; ovarian cancer; tumor reactivity; tumor-infiltrating lymphocyte

DOI:  https://doi.org/10.1007/s11427-025-2958-3
Front Immunol. 2025 ;16 1600863

Revealing the significance of tissue-resident memory T cells in lung adenocarcinoma through bioinformatic analysis and experimental validation.

Zhuoqi Li, Mei Tian, Yuanhui Yang, Yuanyuan Wang, Lu Zhang, Fujing Huang, Xiao Wen, Xiaoshu Yin, Xiaoyan Lin, Yuan Tian.

   Purpose: To investigate the functions of lung TRM cells in the development and treatment of lung adenocarcinoma (LUAD).
Methods: R-language bioinformatics analysis was applied to obtain differentially expressed (DE) lung TRM cell-specific genes and a related prognostic signature, which were further validated using external datasets, immunohistochemical staining images, and biological experiments.
Results: A total of 130 DE lung TRM cell-specific genes were identified, 14 of which were involved in the prognostic signature, including SLC16A3, ARHGAP11A, PTTG1, DTL, GPRIN1, EXO1, GAPDH, TYMS, DAPK2, CCL20, HLA-DQA1, ADAM12, ALOX5AP and OASL. The signature was efficient and robust in predicting the overall survival and anti-PD-1/PD-L1 immunotherapeutic outcomes of patients with LUAD. The AUCs for predicting the 1-, 3-, and 5-year survival rates were 0.688, 0.698, and 0.648, respectively, in the training cohort, and were 0.867, 0.662, and 0.672, respectively, in the validation cohort. The signature also had predictive value for the sensitivity of patients to chemical drugs. TYMS was a hub gene in the prognostic signature, and was strongly associated with LUAD progression and cell proliferation in the experimental validation.
Conclusions: The lung TRM cell-related prognostic signature is an effective tool for predicting the prognosis and therapeutic outcomes of patients with LUAD.

Keywords:  LUAD; TRM cells; TYMS; immunotherapeutic outcomes; prognostic signature

DOI:  https://doi.org/10.3389/fimmu.2025.1600863