Engaging T cell Exhaustion for Solid Tumor Immunotherapies

Cancer immunotherapy, which utilizes the body’s immune system to fight cancer, has the potential to be a highly effective cancer treatment. T-cell-based immunotherapy has also become prominent owing to the success of chimeric antigen receptor-T (CAR-T) cell therapy and immune checkpoint blockade (ICB) therapy. However, due to the complex nature of the tumor microenvironment (TME), T cells struggle to infiltrate solid tumors which limits their effectiveness against many cancers. Chronic antigen exposure also leads to T cell exhaustion—a concept not fully understood.

These three models clearly demonstrated that CD8+ T cells lose their function without IRF4. The functionality of exhausted CD8+T cells is diminished yet sustained due to IRF4 expression. However, when IRF4 is deleted, the diminished CD8+ T cell functions against the tumor are also lost. Transcription factor engineering, specifically, IRF4 engineering, could be an effective approach to enhance adoptive T cell immunotherapies. According to Chen, “Understanding the mechanisms of T cell exhaustion remains a crucial area of research. Our findings have significant implications for advancing more potent immunotherapies that target solid tumors. Further investigations are necessary to elucidate the molecular mechanisms underlying T cell function in human cancers.”

Furthermore, the exact anti-tumor function of CD8+ TILs remains unclear. IRF4 is a crucial transcription factor required for T cell function in both CD4+ and CD8+ subsets. IRF4 expression in T cells is also required for effective anti-tumor immunity. Yet, IRF4 also drives CD8+ T cell exhaustion Hence, Chen questioned whether IRF4 is a good guy or a bad guy. CD8+ T cells, also known as cytotoxic T lymphocytes or killer T cells, play significant roles in fighting against intracellular pathogens as well as tumor cells. T cell exhaustion is a state where T cells (particularly CD8+ T cells) become less functional within the TME after persistent exposure to antigens. As the name suggests, the T cells become exhausted. Although still functional, their effectiveness against tumor cells is diminished. The exhausted CD8+ T cells represent a subpopulation of CD8+ T cells among the repertoire of T cells undergoing differentiation upon immune challenge. CD4+ T cells are more persistent and have more “stemness ” than CD8+ T cells. Notably, CD8+ T cells also have stemness, but they tend to undergo terminal differentiation and are prone to exhaustion. “In the literature, you will not find evidence of CD4+ T cell exhaustion against a tumor,” Chen explained. Whereas CD4+ T cells are important for organ transplant rejection and autoimmune diseases, CD8+ T cells are critical to control tumor growth. CD8+ T cells remain a focal point of cancer research since they can directly kill tumor cells. Chen added, “CD4+ T cells show attributes of resilience and persistence in the context of organ transplantation and autoimmune diseases. This is primarily due to the stemness of CD4+ T cells. However, in contrast to CD4+ T cells, CD8+ T cells do not show these attributes of resilience and persistence against tumor cells. If they did, there would be no tumor.” CD8+ T cells are major effector cells against tumor growth. The process of CD8+ T cell effector differentiation is tightly regulated by metabolic programs, epigenetic modification and transcription factor regulation. The T cell response is acquired and antigen-specific. However, these two attributes do not explain why CD8+ T cells are exhausted. Persistent tumor antigen exposure, continuous activation and various T-cell transcription factors drive T-cell exhaustion. “After antigen exposure, T cells can proliferate three or four times a day,” Chen noted. “One T cell can become eight or 16 T cells in vivo in a day. Extensive proliferation and activation on a continuous basis lead to the T cell exhaustion phenotype which reduces their efficacy against the tumor.” To investigate the transcriptional regulation of CD8+ T cell antitumor immunity, Chen intentionally depleted IRF4 expression in CD8+ T cells in prostate cancer and melanoma murine models. Using IRF4- GFP reporter mice, Chen found that IRF4 is expressed in living exhaustion-like T cells. T cells expressing high levels of IRF4 look like exhausted T cells. In the same IRF4-GFP reporter mice, diphtheria toxin was used to deplete IRF4 expression in T cells, which led to a loss of tumor growth control.

Anze Yu, Jinfei Fu, Zheng Yin, Hui Yan, Xiang Xiao, Dawei Zou, Xiaolong Zhang, Xiongbing Zu, Xian C Li, Wenhao Chen. Continuous Expression of Interferon Regulatory Factor 4 Sustains CD8+ T Cell Immunity against Tumor. Research (Wash D C). 2023 Nov 17:6:0271. doi: 10.34133/research.0271. The research received support from internal fund provided by the Houston Methodist Research Institute to Dr. Wenhao Chen.