bims-tuinly 2025-02-16 papers

Oncol Res Treat. 2025 Feb 12. 1-15

Tumor Infiltrating Lymphocytes, CAR-, and T Cell Receptor- Modified T Cells in Solid Cancer Oncology.

Hakim Echchannaoui, Kevin Jan Legscha, Matthias Theobald.

BACKGROUND: Adoptive cellular therapy (ACT) is a promising treatment approach aiming at enhancing T cell antitumor immune response. ACT includes tumor-infiltrating lymphocytes (TILs), chimeric antigen receptor (CAR) and T-cell receptor (TCR) gene-modified T cells. Despite a milestone achievement with CAR-T cells in hematopoietic malignancies, ACT has shown modest clinical responses in refractory solid cancers and durable responses remain limited to a minor fraction of patients.
SUMMARY: In this review, we highlight major advances, limitations and current developments of T cell therapies for solid cancers. We discuss emerging promising strategies as next-generation ACT, exploring local delivery routes to maximise efficacy and improve safety, integrating predictive biomarkers to optimize selection of patients who most likely would benefit from ACT, using combination therapy to overcome the immunosuppressive tumor microenvironment, targeting multiple tumor antigen to avoid tumor antigen escape, selection of the most potent T cell product to overcome T cell dysfunction and incorporating cutting edge new technologies, such as gene-editing to further improve anti-tumor T cell functions and reduce therapy-related toxicity.
KEY MESSAGES: Advances made in ACT trials have move the field of immunotherapy for refractory solid cancers to a new stage, by constantly incorporating new strategies to develop next-generation therapies designed to enhance efficacy and improve safety and to allow a broaden access to a large numbers of patients.

DOI: https://doi.org/10.1159/000543998

JHEP Rep. 2025 Feb;7(2): 101270

AI-based tumor-infiltrating lymphocyte scoring system for assessing HCC prognosis in patients undergoing liver resection.

Zhiyang Chen, Tingting Xie, Shuting Chen, Zhenhui Li, Su Yao, Xuanjun Lu, Wenfeng He, Chao Tang, Dacheng Yang, Shaohua Li, Feng Shi, Huan Lin, Zipei Li, Anant Madabhushi, Xiangtian Zhao, Zaiyi Liu, Cheng Lu.

Background & Aims: Tumor-infiltrating lymphocytes (TILs), particularly CD8+ TILs, are key prognostic markers in many cancers. However, their prognostic value in hepatocellular carcinoma (HCC) remains controversial, with different evidence. Given the heterogeneous outcomes in patients with HCC undergoing liver resection, this study aims to develop an AI-based system to quantify CD8+ TILs and assess their prognostic value for patients with HCC.
Methods: We conducted a retrospective multicenter study on patients undergoing liver resection across three cohorts (N = 514). We trained a deep neural network and a random forest model to segment tumor regions and locate CD8+ TILs in H&E and CD8-stained whole-slide images. We quantified CD8+ TIL density and established an Automated CD8+ Tumor-infiltrating Lymphocyte Scoring (ATLS-8) system to assess its prognostic value.
Results: In the discovery cohort, the 5-year overall survival (OS) rates were 34.05% for ATLS-8 low-score and 65.03% for ATLS-8 high-score groups (hazard ratio [HR] 2.40; 95% CI, 1.37-4.19; p = 0.015). These findings were confirmed in validation cohort 1, which had 5-year OS rates of 28.57% and 68.73% (HR 3.38; 95% CI, 1.27-9.02; p = 0.0098), and validation cohort 2, which had 59.26% and 81.48% (HR 2.74; 95% CI, 1.05-7.15; p = 0.031). ATLS-8 improved the prognostic model based on clinical variables (C-index 0.770 vs. 0.757; 0.769 vs. 0.727; 0.712 vs. 0.642 in three cohorts).
Conclusions: We developed an automated system using CD8-stained whole-slide images to assess immune infiltration (ATLS-8). In patients with HCC undergoing resection, higher CD8+ TIL density correlates with better OS, as per ATLS-8 assessment. This system is a promising tool for advancing clinical immune microenvironment assessment and outcome prediction.
Impact and implications: CD8+ tumor-infiltrating lymphocytes (TILs) have been identified as a prognostic factor associated with many cancers. In this study, CD8+ TILs were identified as an independent prognostic factor for overall survival in patients with hepatocellular carcinoma who undergoing liver resection. Therefore, ATLS-8, a novel digital biomarker based on whole-slide image-level CD8+ TILs, could play an important role in the prognostic assessment of patients with HCC and could be integrated into clinicopathological models to participate in the decision-making and prognostic assessment of patients. The scoring system combined with artificial intelligence is essential for automated, quantitative, whole-slide image-level assessment of TILs, which can be widely applied to quantify the immune profile of multi-cancer disease types with the discussion of subsequent immunotherapy.

Keywords: Artificial intelligence; Cytotoxic T lymphocyte; Hepatocellular carcinoma; Tumor-infiltrating lymphocyte

DOI: https://doi.org/10.1016/j.jhepr.2024.101270

Semin Oncol Nurs. 2025 Feb 11. pii: S0749-2081(25)00034-8. [Epub ahead of print] 151841

Readiness to Implement Novel SACT: Tumor-Infiltrating Lymphocyte Therapy.

Linda Gomm.

OBJECTIVES: Adoptive cell therapy using tumor-infiltrating lymphocyte (TIL) therapy has demonstrated promising results in clinical trials. Recognizing the growing potential of cell therapies for solid tumors, oncology services need to prepare for an increasing number of trials and, in the near future, optimize patient access to TIL. Consultation with clinical trials professionals in England, however, highlighted low organizational readiness and significant knowledge gaps for use of adoptive cell therapy. The aim of this discussion paper is to provide guidance about the role of the nurse in the delivery of TIL therapy.
METHODS: Guidance was written based on peer-reviewed literature and best practice guidelines between 2006 and 2024 identified through electronic database searches on PubMed, CINAHL, and MEDLINE and expert experience of managing patients in clinical trials who are receiving TIL.
RESULTS: TIL therapy is set to transform current care pathways with treatments that can potentially induce long-lasting tumor responses. There are, however, numerous challenges for successful and safe implementation of TIL therapy in practice. Nurses have a central role in coordinating the safe delivery and patient care of patients receiving TIL therapy. Nurses need knowledge and understanding about the regulatory processes and extensive treatment pathways involved whilst also managing novel side effects and patient expectations.
CONCLUSIONS: TIL therapy requires a specialist team to safely deliver these complex treatments and support colleagues nursing patients receiving TIL therapy. Specialist knowledge and skills and close coordination is required to ensure a smooth process from patient referral, product ordering, manufacturing, storage, and administration of the treatment to the patient.
IMPLICATIONS FOR NURSING PRACTICE: Organizations planning to initiate TIL therapy should review their infrastructure, identify and address specialist knowledge and skills needs of oncology professionals, and seek guidance and support from expert teams. There needs to be a robust governance structure in place and ensure all healthcare professionals involved are trained and educated on a high level on how to care for these patients.

Keywords: Adoptive cell therapy; Advanced nurse practitioner; Lifileucel; Melanoma; Nursing; Symptom management; Tumor-infiltrating lymphocytes

DOI: https://doi.org/10.1016/j.soncn.2025.151841

Cell Death Dis. 2025 Feb 12. 16(1): 90

TIGIT expression in extrahepatic cholangiocarcinoma and its impact on CD8 + T cell exhaustion: implications for immunotherapy.

Tengqian Tang, Wenhao Wang, Lang Gan, Jie Bai, Dehong Tan, Yan Jiang, Ping Zheng, Weijun Zhang, Yu He, Qianfei Zuo, Leida Zhang.

Extrahepatic cholangiocarcinoma (ECCA) is a malignant tumor. The precise role of T-cell immunoreceptor with Ig and ITIM domains (TIGIT), an emerging immunosuppressive receptor, in ECCA, and its impact on CD8+ T cell exhaustion (Tex) remains unclear. We performed single-cell RNA sequencing (scRNA-seq) to characterize tumor-infiltrating lymphocytes (TILs) isolated from ECCA. We found that TIGIT was significantly overexpressed in TOX+CD8 T cells. Tissue microarray and immunohistochemistry staining demonstrated that increased TIGIT expression was associated with poorer patient survival. Flow cytometry analysis revealed that TIGIT+CD8+ T cells exhibited decreased TNF-α, IFN-γ, and TCF-1 expression, accompanied by elevated PD-1 and TIM-3 expression compared to TIGIT-CD8+ T cells. In the patient-derived xenograft (PDX) model, the anti-TIGIT treatment group demonstrated reduced tumor weight, enhanced CD8 frequency, and an increased IFN-γ proportion compared to the PBS treatment group. The TIGIT antibody-treated group exhibited a notably higher fraction of GRZB, and anti-TIGIT treatment led to elevated TCF-1 protein levels and decreased protein levels of TOX1 and NR4A1. Moreover, TIGIT+CD8 T cells from TILs appear to be in a state of exhaustion with low potential killing capacity in ECCA, as shown by scRNA-seq. Taken together, the present study underscores the significant role of TIGIT in ECCA, contributing to T cell exhaustion and a compromised CD8+ T cell immune response. Targeting TIGIT presents a promising therapeutic avenue to enhance the CD8+ T-cell response, thereby potentially improving ECCA therapeutic benefits.

DOI: https://doi.org/10.1038/s41419-025-07388-4

Cold Spring Harb Perspect Med. 2025 Feb 10. pii: a041636. [Epub ahead of print]

Adoptive Cell Therapy for Pediatric Solid Tumors.

Amy B Hont, Catherine M Bollard.

Patients with relapsed or refractory pediatric solid tumors have limited therapeutic options with little to no appreciable improvements in outcomes in over two decades. Adoptive cell therapy (ACT) is a promising, targeted option for patients with the potential to minimize acute and long-term toxicities. In this review, we (1) characterize the development and manufacture different ACT approaches used for pediatric solid tumors, and (2) discuss the obstacles when targeting and treating solid tumors. The outcomes of the clinical applications of the various cell therapy products are also reviewed along with the future potential, including novel product development and combination therapies. In sum, this review serves as a comprehensive review of the clinical trial results evaluating the safety, feasibility, and efficacy of novel cell therapy products in the clinic for the treatment of pediatric solid tumors and seeks to provide new insights regarding ACT successes, failures, and challenges to benefit a rapidly expanding immunotherapy field.

DOI: https://doi.org/10.1101/cshperspect.a041636

Cancers (Basel). 2025 Jan 24. pii: 391. [Epub ahead of print]17(3):

Timing Anti-PD-L1 Checkpoint Blockade Immunotherapy to Enhance Tumor Irradiation.

Steve Seung-Young Lee, Joanna Pagacz, Sera Averbek, David Scholten, Yue Liu, Stephen J Kron.

Background: The ability of radiotherapy (RT) to drive anti-tumor immunity is limited by adaptive resistance. While RT induces inflammation and recruits activated tumor-infiltrating lymphocytes (TILs), including cytotoxic T lymphocytes (CTLs), the resulting radiation- and IFNγ-dependent PD-L1 expression restores an immunosuppressed tumor microenvironment. Unleashing an effective anti-tumor response may require the precise sequencing of RT and checkpoint blockade immunotherapy (CBI) to block PD-L1 signaling before it can mediate its suppressive effects. Methods: Flank tumors formed in BALB/c mice with syngeneic CT26 colon or 4T1 mammary carcinoma cells were treated with otherwise ineffective doses of ionizing radiation (10 Gy) followed by CBI (0.2 mg anti-PD-L1, i.v.) after 0, 1, 3, 5, or 7 days, comparing tumor response. Anti-PD-L1 delivery was measured by fluorescence, TILs by flow cytometry and immunofluorescence, PD-L1 expression by immunohistochemistry, and tumor size by calipers. Results: In both CT26 and 4T1 tumors, 10 Gy alone resulted in a transient growth delay associated with infiltrating CTLs peaking at 3 days and PD-L1 at 5 days. CTLs returned to baseline after 7 days, consistent with adaptive resistance. Anti-PD-L1 failed to potentiate radiation except when injected 5 days after 10 Gy, which prevented CTL depletion and led to tumor elimination. Potentially contributing to compound effects, anti-PD-L1 penetrated tumors and bound PD-L1 more efficiently after irradiation. Conclusions: Optimal timing to exploit radiation-induced permeability to enhance CBI delivery and interrupt adaptive resistance by blocking PD-L1 as it peaks may offer a general strategy to enhance external beam radiotherapy by protecting activated TILs and potentiating anti-tumor immune response.

Keywords: combination immunotherapy; immune checkpoint inhibitor; radiotherapy/radioimmunotherapy

DOI: https://doi.org/10.3390/cancers17030391

Sci Rep. 2025 Feb 08. 15(1): 4716

Infiltration of CD8+ cytotoxic T-cells and expression of PD-1 and PD-L1 in ovarian clear cell carcinoma.

Mengdi Fu, Huimei Zhou, Jiaxin Yang, Dongyan Cao, Zhen Yuan.

Ovarian clear cell carcinoma (OCCC) is resistant to chemotherapy, with limited treatment options for advanced and recurrent disease. The prevalence of OCCC differs by region. Assessing the expression of programmed cell death ligand 1 (PD-L1), PD-1, and CD8+T cell infiltration in OCCC is crucial, as their correlation with patient survival may provide valuable prognostic insights. We collected data from 36 samples from 18 OCCC patients, including 18 pairs of tumors and adjacent nonneoplastic samples. The optimized multiplex immunofluorescence technique was used to stain paraffin sections for immune factors related to the immune microenvironment of OCCC and clinical prognosis. The expression of PDL1 and PD1 in the tumor cells and tumor stromal cells was not significantly correlated with prognosis. Professional quantitative pathological analysis software was used to count the CD8+ cytotoxic T-cells in tumor regions and adjacent nonneoplastic regions in postoperative specimens. There were more CD8+ cytotoxic T-cells in the adjacent nonneoplastic areas than in the tumor tissue samples (p < 0.001). Further analysis revealed that a difference in cell density between CD8+ non-tumor-infiltrating lymphocytes (NTILs) and CD8+ tumor-infiltrating lymphocytes (TILs) exceeding 70 cells/mm2 was associated with poorer progression-free survival (PFS) (p = 0.042). In adjacent nonneoplastic regions, worse PFS was significantly observed in patients with high CD8+ T-cell expression in both total and stromal cells than those with low expression (p = 0.012 vs p = 0.007). The presence of CD8+ T-cells had significant potential for predicting the prognosis of patients with OCCC, which lays a foundation for the development of biomarkers for immune checkpoint blockade treatment response in OCCC patients.

Keywords: CD8+ T-cells; OCCC; PD-1; PD-L1; Progression-free survival

DOI: https://doi.org/10.1038/s41598-025-89270-z