bims-tuinly Biomed News
on Tumor-infiltrating lymphocytes therapy
Issue of 2025–06–01
twelve papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Treatment of patients with pMMR GI cancers with tumor-infiltrating lymphocytes (TIL): a reality?
  2. Cellular Therapy for Advanced Melanoma.
  3. Intratumoral CD8+ tumor-infiltrating lymphocytes as prognostic predictors in radio-chemoradiotherapy-treated nasopharyngeal carcinoma.
  4. Clinical and Fundamental Research Progressions on Tumor-Infiltrating Lymphocytes Therapy in Cancer.
  5. Adoptive T-Cell Therapy in Melanoma: How This Will Impact Surgical Practice and the Role of Surgeons.
  6. Integrating multi-omics data with artificial intelligence to decipher the role of tumor-infiltrating lymphocytes in tumor immunotherapy.
  7. Role of high-dose interleukin-2 for melanoma in the age of cellular therapy.
  8. The role of tumor-infiltrating lymphocytes and depth of invasion in T1 bladder cancer: a retrospective analysis.
  9. Galectin-1 expression in breast cancer stroma - prognostic value in triple-negative breast cancer.
  10. Enhancer-driven gene regulatory networks reveal transcription factors governing T cell adaptation and differentiation in the tumor microenvironment.
  11. The utility of immunohistochemistry-based biomarkers in predicting the pathological complete response in early-stage triple-negative breast cancer.
  12. Combined Biomarkers for Prediction of Immune Checkpoint Inhibitor Response in Patients With Triple-negative Breast Cancer.
  1. Trends Cancer. 2025 May 28. pii: S2405-8033(25)00127-X. [Epub ahead of print]
    Treatment of patients with pMMR GI cancers with tumor-infiltrating lymphocytes (TIL): a reality?
    John B Haanen.
      A recent study published in Nature Medicine shows that adoptive cell therapy using neoantigen-selected tumor-infiltrating lymphocytes (TIL) is feasible in refractory metastatic gastrointestinal (GI) cancers, showing durable responses, especially when combined with anti-PD-1. Despite low tumor mutational burden (TMB), enriched neoantigen-reactive TIL improved objective response rates (ORR), highlighting the role of the tumor microenvironment and supporting further clinical development.
    DOI:  https://doi.org/10.1016/j.trecan.2025.05.004
  2. Surg Clin North Am. 2025 Jun;pii: S0039-6109(25)00018-0. [Epub ahead of print]105(3): 681-690
    Cellular Therapy for Advanced Melanoma.
    Jacob Zaemes, Geoffrey T Gibney.
      Cellular therapy has been an evolving therapeutic approach in advanced melanoma over the past 40 y. The first tumor infiltrating lymphocyte (TIL) therapy, lifileucil, was Food and Drug Administration-approved in 2024 for patients with metastatic melanoma who have previously been treated with an anti-PD-1 therapy and BRAF inhibitor (BRAF V600 mutant disease). Further clinical development of TIL therapy will hopefully lead to safer and more effective strategies. Cellular therapy in melanoma has also expanded beyond TIL therapy with anti-tumor activity demonstrated for TCR-transduced T-cell products and T-cell engager bi-specific agents that target melanoma antigens.
    Keywords:  Cellular therapy; Melanoma; T-cell engager; T-cell therapy; Tumor infiltrating lymphocyte; Tumor infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.suc.2025.03.004
  3. Front Oncol. 2025 ;15 1551980
    Intratumoral CD8+ tumor-infiltrating lymphocytes as prognostic predictors in radio-chemoradiotherapy-treated nasopharyngeal carcinoma.
    Xinjing Li, Xiaoming Qiu, Cuihong Lin, Yuanying Liu, Yongbin Wang, Langlang Tang, Yuanhe Tong, Linbo Tang.
       Background: The prognostic value of tumor-infiltrating lymphocytes (TILs) in nasopharyngeal carcinoma (NPC) has been established. However, the prognostic significance of CD4+ and CD8+ TIL subtypes in NPC remains unclear.
    Methods: We collected 214 tissue samples diagnosed with NPC for immunohistochemical staining. The density of CD4+ and CD8+ TILs was evaluated in intratumoral (within tumor cell nests) and stromal (the surrounding stroma of tumor cell nests) areas. Correlations between TIL density and progression-free survival (PFS) and overall survival (OS) were analyzed.
    Results: High levels of intratumoral CD8+ TILs were significantly associated with reduced risk of disease progression (HR 0.382; 95% CI, 0.178-0.819, P = 0.013) and death (HR 0.265; 95% CI, 0.104-0.675, P = 0.005). Although high stromal CD8+ TIL levels were linked to higher PFS and OS, these differences did not reach statistical significance (P = 0.114 and P = 0.079, respectively). CD4+ TILs showed no significant correlation with PFS or OS. In multivariate analysis, intratumoral CD8+ TILs remained an independent prognostic factor for PFS and OS. Subgroup analysis revealed that in patients with locally advanced disease, high intratumoral CD8+ TILs were significantly associated with improved PFS (HR 0.329; 95% CI, 0.129-0.843, P = 0.021) and OS (HR 0.209; 95% CI, 0.064-0.681, P = 0.009). Conversely, in early-stage patients, neither CD8+ nor CD4+ TILs were significantly associated with PFS or OS.
    Conclusion: Our findings suggest that intratumoral CD8+ TILs serve as a reliable prognostic biomarker for NPC, with their prognostic value particularly pronounced in patients with locally advanced disease.
    Keywords:  CD4; CD8; immunohistochemistry; nasopharyngeal carcinoma; prognosis; tumor-infiltrating lymphocyte
    DOI:  https://doi.org/10.3389/fonc.2025.1551980
  4. Vaccines (Basel). 2025 May 14. pii: 521. [Epub ahead of print]13(5):
    Clinical and Fundamental Research Progressions on Tumor-Infiltrating Lymphocytes Therapy in Cancer.
    Jiandong Hu, Mengli Jin, Weihong Feng, Barbara Nassif-Rausseo, Alexandre Reuben, Chunhua Ma, Gregory Lizee, Fenge Li.
      Malignant tumors represent a significant threat to human health. Among the various therapeutic strategies available, cancer immunotherapy-encompassing adoptive cell transfer (ACT) and immune checkpoint blockade therapy-has emerged as a particularly promising approach following surgical resection, radiotherapy, chemotherapy, and molecular targeted therapies. This form of treatment elicits substantial antigen-specific immune responses, enhances or restores anti-tumor immunity, thereby facilitating the control and destruction of tumor cells, and yielding durable responses across a range of cancers, which can lead to the eradication of tumor lesions and the prevention of recurrence. Tumor-infiltrating lymphocytes (TILs), a subset of ACT, are characterized by their heterogeneity and are found within tumor tissues, where they play a crucial role in mediating host antigen-specific immune responses against tumors. This review aims to explore recent advancements in the understanding of TILs biology, their prognostic implications, and their predictive value in therapeutic contexts.
    Keywords:  clinical response; malignant solid tumor; molecular mechanisms; prognosis; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3390/vaccines13050521
  5. Surg Oncol Clin N Am. 2025 Jul;pii: S1055-3207(25)00002-X. [Epub ahead of print]34(3): 423-436
    Adoptive T-Cell Therapy in Melanoma: How This Will Impact Surgical Practice and the Role of Surgeons.
    R Connor Chick, Joal D Beane, Carlo M Contreras.
      Melanoma is one of a small number of cancers where there is a clear role for surgery in selected patients with metastatic disease. However, the role of surgery for metastatic melanoma in the age of immune checkpoint blockade is not clearly delineated. Adoptive cell therapies, which include tumor-infiltrating lymphocytes and chimeric antigen receptor T cells, often require metastasectomy to obtain the tumor-specific immune cells and/or antigens necessary to create personalized cell-based products. It is, therefore, essential that the surgeon be well-versed in techniques for procuring appropriate tissue and familiar with their delivery to ensure appropriate preoperative planning and postoperative recovery.
    Keywords:  Adoptive cell transfer; CAR-T; Immunotherapy; Tumor infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.soc.2025.01.002
  6. Pathol Res Pract. 2025 May 23. pii: S0344-0338(25)00228-6. [Epub ahead of print]271 156035
    Integrating multi-omics data with artificial intelligence to decipher the role of tumor-infiltrating lymphocytes in tumor immunotherapy.
    Ting Xie, Haochen Xue, Aoling Huang, Honglin Yan, Jingping Yuan.
      Tumor-infiltrating lymphocytes (TILs) are capable of recognizing tumor antigens, impacting tumor prognosis, predicting the efficacy of neoadjuvant therapies, contributing to the development of new cell-based immunotherapies, studying the tumor immune microenvironment, and identifying novel biomarkers. Traditional methods for evaluating TILs primarily rely on histopathological examination using standard hematoxylin and eosin staining or immunohistochemical staining, with manual cell counting under a microscope. These methods are time-consuming and subject to significant observer variability and error. Recently, artificial intelligence (AI) has rapidly advanced in the field of medical imaging, particularly with deep learning algorithms based on convolutional neural networks. AI has shown promise as a powerful tool for the quantitative evaluation of tumor biomarkers. The advent of AI offers new opportunities for the automated and standardized assessment of TILs. This review provides an overview of the advancements in the application of AI for assessing TILs from multiple perspectives. It specifically focuses on AI-driven approaches for identifying TILs in tumor tissue images, automating TILs quantification, recognizing TILs subpopulations, and analyzing the spatial distribution patterns of TILs. The review aims to elucidate the prognostic value of TILs in various cancers, as well as their predictive capacity for responses to immunotherapy and neoadjuvant therapy. Furthermore, the review explores the integration of AI with other emerging technologies, such as single-cell sequencing, multiplex immunofluorescence, spatial transcriptomics, and multimodal approaches, to enhance the comprehensive study of TILs and further elucidate their clinical utility in tumor treatment and prognosis.
    Keywords:  Artificial intelligence; Deep learning; Digital pathology; Machine learning; Tumor microenvironment; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.prp.2025.156035
  7. J Immunother Cancer. 2025 May 30. pii: e011119. [Epub ahead of print]13(5):
    Role of high-dose interleukin-2 for melanoma in the age of cellular therapy.
    Elizabeth Buchbinder, Michael T Lotze, Kim A Margolin, Rodabe Amaria, Amod Sarnaik, Virginia Seery, Zeynep Eroglu, Karam Khaddour, Allison Betof Warner, Harriet M Kluger, Mario Sznol, Michael B Atkins, David F Mcdermott, Ann W Silk.
      Interleukin-2 (IL-2) was one of the first immunotherapies in the treatment of patients with cancer. High-dose bolus IL-2 (HD IL-2) can induce durable complete or partial tumor regression in a small proportion of advanced melanoma and renal cell carcinoma patients. However, its potential for life-threatening side effects and requirement for inpatient administration limits its use to patients with excellent organ function treated at experienced centers. In 2024, following decades of foundational work at the National Cancer Institute, lifileucel became the first FDA-approved tumor-infiltrating lymphocyte (TIL) therapy for cancer. HD IL-2 is routinely given after TIL infusion to promote the survival and proliferation of the T cell product. In this context, fewer doses are given, and the parameters for holding an IL-2 dose are more conservative, as compared with HD IL-2 monotherapy, which has now fallen out of routine use. The lower number of doses, and possibly the effects of the preparative lymphodepletion, result in much less cytokine-related toxicity. Nevertheless, concerns related to HD IL-2 toxicity persist and possibly impact decisions to offer TIL when indicated. Here, we discuss the differences in the administration of HD IL-2 as a monotherapy vs an adjunctive therapy following TIL infusion, in an effort to demystify the toxicity of HD IL-2 in the era of cellular therapy.
    Keywords:  Cytokine; Tumor infiltrating lymphocyte - TIL
    DOI:  https://doi.org/10.1136/jitc-2024-011119
  8. BMC Urol. 2025 May 24. 25(1): 135
    The role of tumor-infiltrating lymphocytes and depth of invasion in T1 bladder cancer: a retrospective analysis.
    Busra Yaprak Bayrak, Hatice Nese Dogan, Kerem Teke, Hakkıcan Yuvak, Ozdal Dillioglugil.
       BACKGROUND: Tumor-infiltrating lymphocytes (TILs) are integral components of the tumor microenvironment and have been extensively studied across various cancers. In bladder cancer, the prognostic significance of TILs remains uncertain. This study aimed to analyze the impact of muscularis mucosa invasion and TILs ratios on clinical outcomes, tumor aggressiveness, and prognosis in pT1 urothelial carcinoma of the bladder.
    METHODS: This retrospective study included 154 patients with pT1 bladder urothelial carcinoma, categorized into pT1a and pT1b groups based on the extent of muscularis mucosa invasion. TILs ratios were stratified into three groups: <1%, 1-5%, and > 5%. Clinical and pathological characteristics, including tumor diameter, necrosis, tumor thickness, recurrence, and progression rates, were compared. Depth of invasion and tumor features were assessed using standard histopathological methods. Recurrence and progression-free survival (PFS) were evaluated during a median follow-up of 20 months.
    RESULTS: By definition, pT1b tumors demonstrated significantly deeper invasion into the muscularis mucosa (p < 0.0001) compared to pT1a tumors. They were also associated with larger tumor diameter (p = 0.023), greater tumor thickness (p < 0.0001), and increased necrosis (p = 0.0012). Radical cystectomy was performed more frequently in pT1b patients (19.2%) than in pT1a patients (7.9%), although recurrence and PFS rates did not differ significantly between the groups. Higher TILs ratios were linked to increased tumor thickness (p = 0.0299) and more extensive invasion into TURBT chips (p = 0.0025), but no significant differences in recurrence or PFS rates were observed across TILs groups.
    CONCLUSIONS: Muscularis mucosa invasion is a defining feature of pT1b bladder cancer and serves as a key indicator of tumor aggressiveness. While TILs were associated with aggressive tumor characteristics, their prognostic role remains inconclusive. These findings highlight the need for aggressive management strategies for pT1b disease and underscore the importance of further research into the complex interplay between TILs and tumor progression in bladder cancer.
    Keywords:  Bladder Cancer; Clinical outcomes; Prognosis; Tumor-infiltrating lymphocytes; Urothelial carcinoma
    DOI:  https://doi.org/10.1186/s12894-025-01822-7
  9. Pathobiology. 2025 May 28. 1-20
    Galectin-1 expression in breast cancer stroma - prognostic value in triple-negative breast cancer.
    Szintia Almási, Tibor Krenács, László Krenács, Gábor Cserni.
       INTRODUCTION: Galectin-1 is a lectin with immunosuppressive effect in different solid tumors. We investigated galectin-1 expression in triple-negative breast cancer (TNBC) to determine its prognostic value.
    METHODS: We examined 95 TNBC surgical samples in tissue microarrays with galectin-1 immunohistochemistry (intensity and percentage of staining) and looked for influences on overall and progression free survivals with the help of Kaplan-Meier estimates. Univariable and multivariable Cox regressions were also analyzed.
    RESULTS: According to Kaplan-Meier curves, a significantly worse overall survival (OS) was found for TNBC patients showing intense or ≥50% galectin-1 stromal interface staining versus those lacking it. Cox regression analyses suggested that galectin-1 expression was an independent prognosticator in TNBC. According to the quantity of stromal tumor-infiltrating lymphocytes (sTILs), significant survival differences depending on galectin-1 status were only seen in the low sTILs (<30%) subset. Multivariable analysis suggested that galectin-1 expression was an independent prognosticator for progression-free survival (PFS).
    DISCUSSION: The immunosuppressive effects of galectin-1 forming a shield around tumor nests may form an immune-escape mechanism and can explain the worse OS and PFS we found in TNBC. Owing to the exploratory nature of the study, the results need confirmation in order to investigate the potentials of anti-galectin-1 therapies.
    DOI:  https://doi.org/10.1159/000546206
  10. Immunity. 2025 May 22. pii: S1074-7613(25)00193-1. [Epub ahead of print]
    Enhancer-driven gene regulatory networks reveal transcription factors governing T cell adaptation and differentiation in the tumor microenvironment.
    William D Green, Amber Gomez, Alec L Plotkin, Brandon M Pratt, Emily F Merritt, Genevieve N Mullins, Nancy P Kren, Jennifer L Modliszewski, Vasyl Zhabotynsky, Mark G Woodcock, Jarred M Green, Gabrielle Cannon, Matthew E Pipkin, Gianpietro Dotti, Jessica E Thaxton, Yuliya Pylayeva-Gupta, Albert S Baldwin, John P Morris, Natalie Stanley, J Justin Milner.
      Tumor-infiltrating lymphocytes (TILs) with a tissue-resident memory CD8+ T cell (Trm) phenotype are associated with improved patient outcomes in solid malignancies. To define programs governing the formation of Trm-like TIL, we performed paired single-cell RNA sequencing and single-cell ATAC sequencing of T cell receptor (TCR)-matched CD8+ T cells in models of infection and cancer. Enhancer-driven regulons assembled from multiomic profiling data revealed epigenetic and transcriptional programs regulating the formation of Trm-like TIL in relation to canonical exhausted and memory T cell states. The transcriptional regulator KLF2 repressed the formation of CD69+CD103+ Trm-like TIL and limited anti-tumor activity. Conversely, sustained expression of the transcription factor BATF enhanced formation of CD69+CD103+ TIL, contingent upon downregulation of KLF2. Transforming growth factor β (TGF-β) signaling and CD103 expression were necessary for Trm-like TIL formation, but BATF overexpression was sufficient to drive formation of CD69+CD103+ TIL in TGFBR2-silenced cells. These findings reveal mechanisms of Trm-like TIL differentiation and provide a framework for considering tissue residency in the context of CD8+ T cell heterogeneity in the tumor microenvironment.
    Keywords:  CD8(+) T cells; exhaustion; immune memory; infection; pancreatic cancer; single-cell multiomics; tissue-resident cells; tumor immunology; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.immuni.2025.04.030
  11. Cancer Treat Res Commun. 2025 May 16. pii: S2468-2942(25)00077-2. [Epub ahead of print]44 100941
    The utility of immunohistochemistry-based biomarkers in predicting the pathological complete response in early-stage triple-negative breast cancer.
    Chikako Funasaka, Takahiro Kogawa, Naoya Sakamoto, Shota Kusuhara, Takehiro Nakao, Hiromichi Nakajima, Chihiro Kondoh, Kenichi Harano, Nobuaki Matsubara, Ako Hosono, Yoichi Naito, Mototsugu Shimokawa, Rurina Watanuki, Yuji Yamashita, Chisako Yamauchi, Tatsuya Onishi, Genichiro Ishii, Toru Mukohara.
      Triple-negative breast cancer (TNBC) is a highly aggressive subtype of BC. A pathological complete response (pCR) to neoadjuvant chemotherapy is strongly associated with a favorable TNBC prognosis; however, established predictors of pCR, including tumor-infiltrating lymphocytes (TILs), are often not adequately reliable in the clinic. This study evaluated the utility of immunohistochemistry (IHC)-based markers and TILs in predicting pCR in early-stage TNBC. This study enrolled 61 women with stage I-III TNBC who were treated at our institution between January 2013 and December 2019. Pathological data were collected from electronic medical records, while IHC data were obtained from preoperative biopsy specimens. Fisher's test, multivariable logistic regression, and correlation analyses were used to identify biomarker candidates and their interactions. The majority of the patients had stage II or III invasive ductal TNBC. The pCR rate was 31 % (19/61). High TIL frequencies (≥ 40 %) and high Ki-67 (≥ 40 %) levels were associated with pCR. Among the patients with high TIL frequencies, AR-negative patients had a higher pCR rate than AR-positive patients (55.0 % versus 16.7 %; p = 0.71). Vimentin negativity correlated with high TIL frequencies (p = 0.02). High TIL frequencies and high Ki-67 levels were independently associated with an increased likelihood of achieving a pCR. The combination of high TIL frequencies and high Ki-67 levels was predictive of pCR in patients with primary TNBC, while AR and vimentin represent candidate markers that require further validation. Further studies should evaluate the performance of these markers in combination with other biomarkers and in the context of immune-checkpoint blockade.
    Keywords:  TIL; Triple-negative breast cancer; neoadjuvant chemotherapy
    DOI:  https://doi.org/10.1016/j.ctarc.2025.100941
  12. Anticancer Res. 2025 Jun;45(6): 2575-2586
    Combined Biomarkers for Prediction of Immune Checkpoint Inhibitor Response in Patients With Triple-negative Breast Cancer.
    Han Gyeol Kim, So Young Kang, Kyoung-Mee Kim, Ji-Yeon Kim, Yeon Hee Park, Jin Seok Ahn, Young-Hyuck Im, Yoojoo Lim, Sanghoon Song, Kyunghyun Paeng, Eun Yoon Cho.
       BACKGROUND/AIM: Triple-negative breast cancer (TNBC) is an aggressive malignancy with few available targeted therapies. In this study, we examined the predictive power of several biomarkers, comprising the IMmunotherapy Against GastrIc Cancer (IMAGiC) model, PD-L1 combined positive score (CPS), intra-tumoral tumor-infiltrating lymphocytes (iTILs), and stromal TILs (sTILs), in an Asian population of patients with metastatic TNBC treated with immunotherapy.
    PATIENTS AND METHODS: Thirty-one metastatic TNBC patients receiving immunotherapy were analyzed. For measuring expression levels of the mRNA of four immune-related genes in the IMAGiC test, quantitative real-time polymerase chain reaction was used. TIL detection and quantification were conducted using Lunit SCOPE IO, which is an AI-powered spatial TIL analyzer.
    RESULTS: Patients were classified into IMAGiC responder and non-responder groups according to IMAGiC score cut-off value. There were significantly more clinical responders [complete (CR) or partial (PR) response] in the IMAGiC responder group than in the IMAGiC non-responder group (50% vs. 15.3%, p=0.05). Area under the curve (AUC) values were calculated to examine the predictive value of the IMAGiC score, PD-L1 CPS, iTILs, and sTILs, for response to immunotherapy. The AUC values of the IMAGiC group and score were 0.684 and 0.632, respectively. When the IMAGiC group and iTIL level were combined, the highest AUC value of 0.755 was obtained.
    CONCLUSION: The combination of IMAGiC and iTILs as a biomarker can guide clinical decisions in the immunotherapy of metastatic TNBCs.
    Keywords:  Biomarker; immune checkpoint inhibitors; triple-negative breast cancer; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.21873/anticanres.17629
This page is being maintained by Thomas Krichel. It was last updated on 2025‒06‒01 at 4:33.