Induction of tissue-resident TFH-like cells in human cancer links monocyte activation to M2b macrophage polarization (TUM10P.1021)

Abstract The existence, regulation, and functions of IL-21+ immune cells are poorly defined in human cancers. Here we identified a subset of protumorigenic IL-21+ TFH-like cells in human hepatocellular carcinoma. These cells were the major source of IL-21 in tumors and represented about 10% of the CD4+ T cell population at levels comparable to amounts of TFH cells present in lymph nodes. However, the TFH-like cells displayed a unique CXCR5−PD-1−BTLA−CD69high tissue-resident phenotype with substantial IFN-γ production, which differed from the phenotype of TFH cells. TLR4-elicited innate monocyte inflammation was essential for IL-21+ TFH-like cell induction in tumors, and activation of STAT1 and STAT3 was critical for TFH-like cell polarization in this process. Importantly, the TFH-like cells operated in IL-21-IFN-γ-dependent pathways to induce plasma cell differentiation and thereby create conditions for M2b macrophage polarization. Thus induction of TFH-like cells links innate inflammation to immune privilege in tumors.