Continuous Expression of Interferon Regulatory Factor 4 Sustains CD8 T Cell Immunity against Tumor.

T-cell-based immunotherapy is gaining momentum in cancer treatment; however, our comprehension of the transcriptional regulation governing T cell antitumor activity remains constrained. The objective of this study was to explore the function of interferon regulatory factor 4 (IRF4) in antitumor CD8 T cells using the TRAMP-C1 prostate cancer and B16F10 melanoma model. To achieve this, we generated an mouse strain and discovered that CD8 tumor-infiltrating lymphocytes (TILs) expressing high levels of IRF4.GFP exhibited a more differentiated PD-1 cell phenotype. By administering diphtheria toxin to tumor-bearing mice, we partially depleted IRF4.GFP TILs and observed an accelerated tumor growth. To specifically explore the function of IRF4 in antitumor CD8 T cells, we conducted 3 adoptive cell therapy (ACT) models. Firstly, depleting IRF4.GFP CD8 TILs derived from ACT significantly accelerated tumor growth, emphasizing their crucial role in controlling tumor progression. Secondly, deleting the gene in antitumor CD8 T cells used for ACT led to a reduction in the frequency and effector differentiation of CD8 TILs, completely abolishing the antitumor effects of ACT. Lastly, we performed a temporal deletion of the gene in antitumor CD8 T cells during ACT, starting from 20 days after tumor implantation, which significantly compromised tumor control. Therefore, sustained expression of IRF4 is essential for maintaining CD8 T cell immunity in the melanoma model, and these findings carry noteworthy implications for the advancement of more potent immunotherapies for solid tumors.