Background: Checkpoint inhibitors act on exhausted CD8 T cells and restore their effector function in chronic infections and cancer. The underlying mechanisms of action appear to differ between different types of cancer and are not yet fully understood.
Methods: Here, we established a new orthotopic HCC model to study the effects of checkpoint blockade on exhausted CD8 tumor-infiltrating lymphocytes (TILs). The tumors expressed endogenous levels of HA, which allowed the study of tumor-specific T cells.
Results: The induced tumors developed an immune-resistant TME in which few T cells were found. The few recovered CD8 TILs were mostly terminally exhausted and expressed high levels of PD-1. PD-1/CTLA-4 blockade resulted in a strong increase in the number of CD8 TILs expressing intermediate amounts of PD-1, also called progenitor-exhausted CD8 TILs, while terminally exhausted CD8 TILs were almost absent in the tumors of treated mice. Although transferred naïve tumor-specific T cells did not expand in the tumors of untreated mice, they expanded strongly after treatment and generated progenitor-exhausted but not terminally exhausted CD8 TILs. Unexpectedly, progenitor-exhausted CD8 TILs mediated the antitumor response after treatment with minimal changes in their transcriptional profile.
Conclusion: In our model, few doses of checkpoint inhibitors during the priming of transferred CD8 tumor-specific T cells were sufficient to induce tumor remission. Therefore, PD-1/CTLA-4 blockade has an ameliorative effect on the expansion of recently primed CD8 T cells while preventing their development into terminally exhausted CD8 TILs in the TME. This finding could have important implications for future T-cell therapies.
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http://dx.doi.org/10.1159/000526899 | DOI Listing |
Front Immunol
December 2024
Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians University, Munich, Germany.
CD8+ T cells are crucial cytotoxic components of the tumor immune system. In chronic inflammation, they become low-responsive, a state known as T cell exhaustion (TEX). The aim of immune checkpoint blockade is to counteract TEX, yet its dynamics in breast cancer remain poorly understood.
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December 2024
Division of Gastroenterology, Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, 101, Daehak-Ro, Jongno-Gu, Seoul, Republic of Korea.
Pancreatic cancer is influenced by interactions between cancer cells and the tumor microenvironment (TME), including tumor-infiltrating lymphocytes (TILs). Specifically, CD8 + T cells impact prognosis by eliminating cancer cells. Recent studies have revealed that microbiomes are present in pancreatic tissues and may affect tumor growth and immune responses.
View Article and Find Full Text PDFFront Immunol
December 2024
SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield, South Africa.
Malignant melanoma, the most aggressive form of skin cancer, is characterized by unpredictable growth patterns, and its mortality rate has remained alarmingly high over recent decades, despite various treatment approaches. One promising strategy for improving outcomes in melanoma patients lies in the early use of biomarkers to predict prognosis. Biomarkers offer a way to gauge patient outlook early in the disease course, facilitating timely, targeted intervention.
View Article and Find Full Text PDFTransl Oncol
December 2024
Biotherapy Center, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, China. Electronic address:
It has been well established that tumor-infiltrating lymphocytes (TILs) play a critical role in the pathogenesis and progression of clear cell renal cell carcinoma (ccRCC). However, the mechanism on the interactions between TILs and tumor cells in the tumor-immune microenvironment remains unclear. In the present study, the expression of Response Gene to Complement 32 (RGC-32) was evaluated using immunohistochemistry.
View Article and Find Full Text PDFCell Syst
December 2024
Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Institute of Materials Science & Engineering, EPFL, 1015 Lausanne, Switzerland. Electronic address:
Many cancer immunotherapies rely on robust CD8 T cells capable of eliminating cancer cells and establishing long-term tumor control. Recent insights into immunometabolism highlight the importance of nutrients and metabolites in T cell activation and differentiation. Within the tumor microenvironment (TME), CD8 tumor-infiltrating lymphocytes (TILs) undergo metabolic adaptations to survive but compromise their effector function and differentiation.
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