Work

Mechanisms of CD4-help that enhance anti-tumor responses 3246

Year: 2025

Type: article

Abstract: Description CD8 T cells are crucial in cancer immunotherapy, but CD4 T cells also impact outcomes. Our studies in hepatocellular carcinoma (HCC) patients suggested that response to PD-1 blockade was driven by the intratumoral expansion of follicular helper-like CD4 T cells (Tfhl), which enhanced interactions of progenitor exhausted CD8 T cells (Tpex) with activated dendritic cells (DC) to mediate effector-like CD8 T cell differentiation. To mechanistically dissect the role of CD4-help during PD-1 blockade we developed a novel mouse model of HCC. Tumor-specific CD8 T cells exhibited similar subsets as patients. All tumor-infiltrating PD-1+ CD4 T cells expressed Tbet, but were either TCF-1 + (with Tfhl features) or CD39 + (with canonical Th1 markers). Tumors were unresponsive to PD-1 blockade, unless CD4-help was enhanced by transfer of a small number of tumor-specific CD4 T cells. In HCC CD4 helped mice, PD-1 blockade increased tumor-specific Tpex, CD4+ Tfhl phenotype, and tumor-specific antibodies, resulting in significant survival and complete responses in more than 50% of mice. To further address the role of helper programs we delete Tbet and Bcl6 on tumor-specific CD4 T cells. To understand the role of antibodies in tumor control we use B-cell restricted mouse strains. Overall, our findings highlight the role of Tfhl in sensitizing tumors to overcome resistance to PD-1 blockade and provide mechanistic insights of coordinated cell interactions for effective anti-tumor control. Funding Sources Tisch Cancer Institute Cancer Center Support Grant (P30 CA196521) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.1064