bims-tuinly 2025-03-16 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–03–16
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Distinct CD8+ T cell dynamics associate with response to neoadjuvant cancer immunotherapies.
Migration of Regulatory T Cells to the Peritumor Microenvironment of Experimental Glioblastoma.
Composite score of PD-1 + CD8 + tumor-infiltrating lymphocytes and CD57 + CD8 + tumor ascites lymphocytes is associated with prognosis and tumor immune microenvironment of patients with advanced high-grade serous ovarian cancer.
Evaluating the Tumor Burden, Histological Changes, and Immune Landscape of Breast Cancer Post-neoadjuvant Chemotherapy: Insights From 50 Cases.
Colorectal Carcinoma: Is There Any Correlation between Her2/neu Expression, Ki-67 Score, and Tumor Budding and Clinicopathological Parameters?-A Prospective Institution-Based Study.
Automated deep learning-based assessment of tumour-infiltrating lymphocyte density determines prognosis in colorectal cancer.
Research progress of T cells in cholangiocarcinoma.
Impacts of ageing on the efficacy of CAR-T cell therapy.
Bispecific T-cell engagers for the recruitment of T cells in solid tumors: a literature review.
The Emerging Role of CD8+ T Cells in Shaping Treatment Outcomes of Patients with MDS and AML.

Cancer Cell. 2025 Mar 12. pii: S1535-6108(25)00078-9. [Epub ahead of print]

Distinct CD8+ T cell dynamics associate with response to neoadjuvant cancer immunotherapies.

Housaiyin Li, Dan P Zandberg, Aditi Kulkarni, Simion I Chiosea, Patricia M Santos, Brian R Isett, Marion Joy, Gabriel L Sica, Kevin J Contrera, Curtis M Tatsuoka, Matthias Brand, Umamaheswar Duvvuri, Seungwon Kim, Mark Kubik, Shaum Sridharan, Fei Tu, Jie Chen, Tullia C Bruno, Dario A A Vignali, Anthony R Cillo, Riyue Bao, Jing Hong Wang, Lazar Vujanovic, Robert L Ferris.

  We leverage a clinical trial (NCT04080804) that compared neoadjuvant anti-PD-1, anti-PD-1+CTLA-4, and anti-PD-1+LAG-3 therapies in head and neck squamous cell carcinoma patients. Combination therapies promote higher pathologic response rates versus monotherapy, and major pathologic response is associated with better survival. To address whether successful immune checkpoint inhibitor (ICI) regimens act through similar or distinct pathways, we robustly and longitudinally characterize transcriptional and proteomic dynamics of CD8+ tumor-infiltrating lymphocytes (TILs) in a clonal manner. Anti-PD-1+LAG-3 reprograms CD8+ TIL with type-I interferon response and exhaustion gene programs into effector memory and resident memory (TEM/TRM). In contrast, anti-PD-1+CTLA-4 activates and expands pre-existing TEM/TRM CD8+ TIL, but does not rejuvenate exhausted phenotypes into T effector cells. Anti-PD-1+LAG-3, but not anti-PD-1+CTLA-4, induces widespread TCR sharing among the different transcriptional states, as well as increased TCR diversity in responding patients. Our data suggest doublet regimen-specific transcriptional and clonal dynamics of tumor-reactive CD8+ T cells.

Keywords:  CTLA-4; Head and neck cancer; LAG-3; PD-1; T cell dynamics; clinical trial; combination immunotherapy; multispectral imaging; single-cell genomics; tumor immunology

DOI:  https://doi.org/10.1016/j.ccell.2025.02.026
Sovrem Tekhnologii Med. 2025 ;17(1): 70-78

Migration of Regulatory T Cells to the Peritumor Microenvironment of Experimental Glioblastoma.

E P Yanysheva, P A Melnikov, D A Chudakova, M V Shirmanova, V P Baklaushev, G M Yusubalieva.

  Glioblastoma is the most aggressive primary brain tumor with poor prognosis characterized by resistance to standard treatments and immune evasion. Regulatory T lymphocytes (Tregs) play a key role in immune suppression in the tumor microenvironment and can be used as targets for malignant gliomas therapy. The aim of the investigation is to study migration of Tregs to the tumor site in the process of dynamic glioblastoma growth on the transgenic C57Bl/6-FoxP3-eGFP mouse line.
Materials and Methods: The study was performed using the C57Bl/6-FoxP3-eGFP mouse strain, which allows for the detection of FoxP3-positive Tregs by fluorescent signal. Orthotopic glioblastomas were implanted by stereotactic injection of fluorescently labeled GL-261-BFP and GL-261-mScarlet tumor cell lines. Intravital confocal microscopy was used to monitor infiltration of the tumor site by immune cells, visualized by intravenous injection of fluorescently labeled antibodies against CD45. The results of intravital microscopy were confirmed by histological and immunohistochemical examination on days 3, 6, 9, 14, and 16 after the implantation. To assess the immunological status, tumor-infiltrating lymphocytes (TILs) were isolated from the brain and Tregs were counted using a flow cytometer (immediately after isolation and after cultivation for 2 weeks).
Results: Intravital microscopy and brain slice studies have demonstrated infiltration of the glioblastoma site by Tregs, with the proportion of Tregs increasing with tumor progression (the increase in the absolute number of Treg was proportional to the increase in the number of glioma cells). Subsequent co-cultivation of isolated TILs with glioma cells revealed increase of Treg population within 2 weeks from 2.8% to >40%, confirming the activating effect of glioblastoma with respect to Tregs.
Conclusion: The dynamics of GL-261 glioma microenvironment infiltration by Tregs has been investigated. The glioblastoma cells were shown to activate Tregs in the peritumor space in vivo and to promote their selective expansion when co-cultured with TILs in vitro. These data can be used for further studies on C57Bl/6-FoxP3-eGFP mice to find approaches to inactivate Tregs in glioblastoma.

Keywords:  glioblastoma; glioma; migration; regulatory T lymphocytes; tumor; tumor microenvironment

DOI:  https://doi.org/10.17691/stm2025.17.1.07
Chin J Cancer Res. 2025 Jan 30. 37(1): 73-89

Composite score of PD-1 + CD8 + tumor-infiltrating lymphocytes and CD57 + CD8 + tumor ascites lymphocytes is associated with prognosis and tumor immune microenvironment of patients with advanced high-grade serous ovarian cancer.

Tianhui He, Jie Zhang, Lin Zeng, Zhongnan Yin, Bo Yu, Xi Zhang, Xiaoxue Yang, Chunliang Shang, Lixiang Xue, Hongyan Guo.

   Objective: The expression of programmed death 1 (PD-1) on CD8+ T cells is associated with their activation and exhaustion, while CD57 serves as a senescence marker. The impact of PD-1+ and CD57+CD8+ T cells on the prognosis of patients with advanced high-grade serous ovarian cancer (HGSOC) remain unclear.
Methods: We assessed the percentages of PD-1+ and CD57+CD8+ T cells in tumor-infiltrating lymphocytes (TILs, n=85) and tumor ascites lymphocytes (TALs, n=87) using flow cytometry. The optimal cutoffs for these markers in TILs and TALs were determined through the log-rank maximization method. Gene expression analysis elucidated the tumor immune microenvironment (TIME, n=36).
Results: Patients with higher PD-1+CD8+ TILs (>87.8%) exhibited longer platinum-free interval (PFI) and overall survival (OS). In contrast, those with elevated CD57+CD8+ TALs (>28.69%) were more likely to experience chemotherapy and had lower complete remission rates, shorter PFI and OS. PD-1+CD8+ TILs are primarily displayed an effector memory state with strong proliferative and secretory capabilities. Approximately 50% of CD57+CD8+ TALs were terminally differentiated, exhibiting significantly impaired proliferation. Based on the proportions of PD-1+CD8+ TILs and CD57+CD8+ TALs, patients were categorized into good, median and poor prognosis groups, with median PFI of 47.78, 27.29 and 11.96 months, respectively (P<0.0001). Median OS for these groups was not reach, 49.23 and 30.92 months, respectively (P<0.0001). Patients with poor prognosis exhibit significantly reduced CD8+ T cell proportion and increased M2 macrophage in the TIME, alongside downregulation of multiple T cell activation-related pathways.
Conclusions: Lower levels of PD-1+CD8+ TILs and higher CD57+CD8+ TALs, assessed prior to treatment, correlated with poor prognosis and suppressive TIME in advanced HGSOC.

Keywords:  CD57+CD8+ T cells; High-grade serous ovarian cancer; PD-1+CD8+ T cells; biomarker; prognosis

DOI:  https://doi.org/10.21147/j.issn.1000-9604.2025.01.06
Cureus. 2025 Mar;17(3): e80258

Evaluating the Tumor Burden, Histological Changes, and Immune Landscape of Breast Cancer Post-neoadjuvant Chemotherapy: Insights From 50 Cases.

Arasi Rajesh, Dharma Saranya Gurusamy, Rajalakshmi Manikkam.

  Breast cancer is a heterogeneous disease with variable responses to neoadjuvant chemotherapy (NACT). Evaluating the histopathological and immune changes in post-NACT breast cancer specimens is crucial for understanding treatment response and guiding further management. This study aims to assess tumor burden using the Residual Cancer Burden (RCB) index, examine histological alterations, evaluate immune activity through tumor-infiltrating lymphocytes (TILs), and analyze proliferative capacity via Ki-67 expression in post-NACT breast cancer specimens. A cross-sectional study of 50 modified radical mastectomy (MRM) specimens post-NACT was conducted. The histopathological analysis included tumor regression changes, stromal and cellular alterations, and nodal involvement. Immune response was assessed by quantifying TILs, and proliferation was measured using the Ki-67 index. Statistical correlations were made between clinicopathological parameters, TILs, and Ki-67 expression. Residual disease was detected in 39 cases (78%), and 11 cases (22%) had no residual disease. Among the 39 cases with residual disease, the majority were classified as RCB II (22 cases, 56%), 16 cases (41%) were classified as RCB III, and one case (3%) was classified as RCB I. Common histological changes post-NACT included fibrosis in 31 cases (62%), necrosis in 19 cases (38%), and infiltration by foamy histiocytes in 16 cases (32%). Malignant epithelial cells more frequently exhibited foamy cytoplasm (16 cases (41%) vs. two cases (5%); p=0.0003), hyperchromatic nucleus (26 cases (67%) vs. six cases (15%); p=0.0001), and prominent nucleoli (26 cases (67%) vs. four cases (10%); p=0.0001) compared to benign cells. Among the 39 cases with residual disease, low TIL and high Ki-67 expression were observed in 20 cases (51%), while 12 cases (32%) showed high TIL and low Ki-67. Residual tumors with high TIL and high Ki-67 (four cases, 10%) and low TIL and low Ki-67 (three cases, 8%) were less common. A significant inverse relationship was found between TIL levels and Ki-67 expression (p=0.0002), as tumors with low TIL were more likely to have high Ki-67 expression (20 cases, 51%), whereas those with high TIL more frequently exhibited low Ki-67 expression (12 cases, 32%). Post-NACT evaluation of tumor burden, immune landscape, and proliferation provides valuable prognostic insights. Integrating RCB, TILs, and Ki-67 into routine pathological assessment may aid patient stratification and guide personalized treatment strategies. Further large-scale studies are needed to validate these findings and improve therapeutic decision-making in breast cancer management.

Keywords:  breast cancer; immune response; post-neoadjuvant chemotherapy; proliferation index; residual cancer burden; tumor regression; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.7759/cureus.80258
South Asian J Cancer. 2024 Oct;13(4): 320-324

Colorectal Carcinoma: Is There Any Correlation between Her2/neu Expression, Ki-67 Score, and Tumor Budding and Clinicopathological Parameters?-A Prospective Institution-Based Study.

Susnata Khan, Senjuti Dasgupta, Asit Ranjan Deb.

   Objectives: Colorectal cancer is one of the most frequent cancers worldwide and is still a major cause of cancer mortality. Her2/neu, Ki67 score, and tumor budding are independent prognostic factors in colorectal carcinomas. The objectives of the study were to evaluate Her2/neu expression, Ki67 score, and tumor budding index at invasive margin in colorectal carcinoma and find out their possible correlations with different clinicopathological factors.
Materials and Methods: An institution-based observational cross-sectional study was conducted for 18 months. Forty-one patients with histologically proven diagnosis of colorectal carcinoma were included. Histopathological and immunohistochemical analyses (Her2/neu and Ki-67) of each case were done.
Statistical Analysis: Data analysis was done using the SPSS software.
Results: A significant correlation was found between tumor budding status and pathological T stage, Dukes' and American Joint Committee on Cancer stages, and between tumor-infiltrating lymphocytes status and Ki-67 expression status ( p < 0.05).
Conclusion: The prognostic importance of tumor budding in colorectal carcinoma is very clear. Considering the small sample size of the present study, the prognostic values of Her2/neu and Ki-67 are required to be explored further in larger cohorts in the future.

Keywords:  Her2/neu; Ki-67; colorectal carcinoma; tumor budding; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1055/s-0044-1789276
J Transl Med. 2025 Mar 10. 23(1): 298

Automated deep learning-based assessment of tumour-infiltrating lymphocyte density determines prognosis in colorectal cancer.

Joshua Millward, Zhen He, Aiden Nibali, Dmitri Mouradov, Lisa A Mielke, Kelly Tran, Angela Chou, Nicholas J Hawkins, Robyn L Ward, Anthony J Gill, Oliver M Sieber, David S Williams.

   BACKGROUND: The presence of tumour-infiltrating lymphocytes (TILs) is a well-established prognostic biomarker across multiple cancer types, with higher TIL counts being associated with lower recurrence rates and improved patient survival. We aimed to examine whether an automated intraepithelial TIL (iTIL) assessment could stratify patients by risk, with the ability to generalise across independent patient cohorts, using routine H&E slides of colorectal cancer (CRC). To our knowledge, no other existing fully automated iTIL system has demonstrated this capability.
METHODS: An automated method employing deep neural networks was developed to enumerate iTILs in H&E slides of CRC. The method was applied to a Stage III discovery cohort (n = 353) to identify an optimal threshold of 17 iTILs per-mm2 tumour for stratifying relapse-free survival. Using this threshold, patients from two independent Stage II-III validation cohorts (n = 1070, n = 885) were classified as "TIL-High" or "TIL-Low".
RESULTS: Significant stratification was observed in terms of overall survival for a combined validation cohort univariate (HR 1.67, 95%CI 1.39-2.00; p < 0.001) and multivariate (HR 1.37, 95%CI 1.13-1.66; p = 0.001) analysis. Our iTIL classifier was an independent prognostic factor within proficient DNA mismatch repair (pMMR) Stage II CRC cases with clinical high-risk features. Of these, those classified as TIL-High had outcomes similar to pMMR clinical low risk cases, and those classified TIL-Low had significantly poorer outcomes (univariate HR 2.38, 95%CI 1.57-3.61; p < 0.001, multivariate HR 2.17, 95%CI 1.42-3.33; p < 0.001).
CONCLUSIONS: Our deep learning method is the first fully automated system to stratify patient outcome by analysing TILs in H&E slides of CRC, that has shown generalisation capabilities across multiple independent cohorts.

Keywords:  Cell detection; Computational pathology; Image analysis; Tissue segmentation

DOI:  https://doi.org/10.1186/s12967-025-06254-3
Front Immunol. 2025 ;16 1453344

Research progress of T cells in cholangiocarcinoma.

Zhiming Wang, Yunyan Dai, Yunpeng Zhou, Yi Wang, Pinggui Chen, Yaoxuan Li, Yunfei Zhang, Xiaocui Wang, Ying Hu, Haonan Li, Gaopeng Li, Yukai Jing.

  Cholangiocarcinoma (CCA), a malignant tumor, is typically challenging to detect early and often results in a poor prognosis. In recent years, research interest has grown in the potential application of immunotherapy for CCA treatment. T cells, as a crucial component of the immune system, play a significant role in immune surveillance and therapy for cholangiocarcinoma. This article provides a review of the research advancements concerning T cells in cholangiocarcinoma patients, including their distribution, functional status, and correlation with patient prognosis within the tumor microenvironment. It further discusses the potential applications and challenges of immunotherapy strategies targeting T cells in CCA treatment and anticipates future research directions. A more profound understanding of T cells' role in cholangiocarcinoma can guide the development of clinical treatment strategies, thereby enhancing patient survival rates and quality of life. Finally, we explored the potential risks and side effects of immunotherapy for T-cell cholangiocarcinoma.

Keywords:  T lymphocytes; cholangiocarcinoma; immunization checkpoints; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1453344
Ageing Res Rev. 2025 Mar 07. pii: S1568-1637(25)00061-3. [Epub ahead of print] 102715

Impacts of ageing on the efficacy of CAR-T cell therapy.

Shimao Qi, Jiaqian Li, Xinyu Gu, Yalan Zhang, Weilin Zhou, Fengling Wangand Wei Wang.

  Chimeric antigen receptor T cells recognizing CD19 (19CAR-T) cell therapy has achieved robust clinical efficacy when treating some hematological malignancies, but which patient subgroups benefit mostly remains elusive. Here we summarized the data of 541 patients from 30 clinical trials who underwent 19 CAR-T therapy and analyzed the different clinical responses between young (<44 years), middle-aged (45-59 years) and elderly (>60 years) patients and found that the young patients showed a higher level of complete response (CR) rate. Therefore, we then summarize the advances of studies focusing on the effects of age on anti-tumor efficacy of CAR-T therapy and analyze the reasons for the low CR rate after CAR-T cell therapy in elderly patients with tumors, aiming to provide hints for oncologists to select the most suitable candidate for this cancer immunotherapy.

Keywords:  CAR-T cell; CD19; ageing; clinical effect; tumor microenvironment

DOI:  https://doi.org/10.1016/j.arr.2025.102715
Immunother Adv. 2025 ;5(1): ltae005

Bispecific T-cell engagers for the recruitment of T cells in solid tumors: a literature review.

Laura Dewaele, Ricardo A Fernandes.

  In the past decade, T-cell-based immunotherapies have grown to become some of the most promising treatments for cancer. Following the success of immune checkpoint inhibitors, other T-cell-based therapies emerged including CAR-T cells and bispecific T-cell engagers (BiTEs). BiTEs have the unique ability to crosslink T cells and tumor cells independently of major histocompatibility complex (MHC) restriction. They do not rely on TCR specificity or the CD4+/CD8+ costimulatory molecules, overcoming tumor MHC downregulation and low-affinity TCR binding. However, like many other immunotherapies, BiTEs have shown limited success beyond the treatment of hematological malignancies. BiTEs for the treatment of solid tumors still face challenges. Studies in gastrointestinal tumors have revealed Fc toxicity, short half-lives, and immunotoxicity, leading to Fc-silenced half-life extended BiTEs with humanized single-chain variable fragments. Studies in prostate tumors, lung tumors, and malignant gliomas have identified promising targets in PSMA, DLL3, and EGFRvIII, respectively, but also highlighted the problems of on-target off-tumor and BiTE-specific toxicities and inaccessible or immunosuppressive tumor microenvironments. Ongoing research to overcome these limitations remains an interesting field to follow, as BiTEs have the potential to be a powerful tool, especially when used in combination with other immunotherapies.

Keywords:  BiTEs; T-cell; bispecific; tumors

DOI:  https://doi.org/10.1093/immadv/ltae005
Cancers (Basel). 2025 Feb 22. pii: 749. [Epub ahead of print]17(5):

The Emerging Role of CD8+ T Cells in Shaping Treatment Outcomes of Patients with MDS and AML.

Athanasios Tasis, Theodoros Spyropoulos, Ioannis Mitroulis.

  CD8+ T cells are critical players in anti-tumor immunity against solid tumors, targeted by immunotherapies. Emerging evidence suggests that CD8+ T cells also play a crucial role in anti-tumor responses and determining treatment outcomes in hematologic malignancies like myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). In this review, we focus on the implication of CD8+ T cells in the treatment response of patients with MDS and AML. First, we review reported studies of aberrant functionality and clonality of CD8+ T cells in MDS and AML, often driven by the immunosuppressive bone marrow microenvironment, which can hinder effective antitumor immunity. Additionally, we discuss the potential use of CD8+ T cell subpopulations, including memory and senescent-like subsets, as predictive biomarkers for treatment response to a variety of treatment regimens, such as hypomethylating agents, which is the standard of care for patients with higher-risk MDS, and chemotherapy which is the main treatment of patients with AML. Understanding the multifaceted role of CD8+ T cells and their interaction with malignant cells in MDS and AML will provide useful insights into their potential as prognostic/predictive biomarkers, but also uncover alternative approaches to novel treatment strategies that could reshape the therapeutic landscape, thus improving treatment efficacy, aiding in overcoming treatment resistance and improving patient survival in these challenging myeloid neoplasms.

Keywords:  CD8+ T cells; acute myeloid leukemia (AML); allogenic hematopoietic stem cell transplantation (allo-HSCT); chemotherapy; exhaustion; hypomethylating agents (HMAs); immunotherapy; myelodysplastic neoplasms (MDS); senescence; treatment response

DOI:  https://doi.org/10.3390/cancers17050749