Research (Jan 2023)
Continuous Expression of Interferon Regulatory Factor 4 Sustains CD8+ T Cell Immunity against Tumor
Abstract
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 Irf4GFP-DTR mouse strain and discovered that CD8+ tumor-infiltrating lymphocytes (TILs) expressing high levels of IRF4.GFP exhibited a more differentiated PD-1high cell phenotype. By administering diphtheria toxin to tumor-bearing Irf4GFP-DTR 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 Irf4 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 Irf4 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.