Polarization of Tissue-Resident TFH-Like Cells in Human Hepatoma Bridges Innate Monocyte Inflammation and M2b Macrophage Polarization.

The existence, regulation, and functions of IL21+ immune cells are poorly defined in human cancers. Here, we identified a subset of protumorigenic IL21+ TFH-like cells in human hepatocellular carcinoma. These cells were the major source of IL21 in tumors and represented about 10% of the CD4+ T-cell population at levels comparable with the TFH cells present in lymph nodes. However, these TFH-like cells displayed a unique CXCR5-PD-1lo/-BTLA-CD69hi tissue-resident phenotype with substantial IFNγ production, which differed from the phenotype of TFH cells. Toll-like receptor 4 (TLR4)-elicited innate monocyte inflammation was important for IL21+ 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 IL21-IFNγ-dependent pathways to induce plasma cell differentiation and thereby create conditions for protumorigenic M2b macrophage polarization and cancer progression. Thus, induction of TFH-like cells links innate inflammation to immune privilege in tumors. SIGNIFICANCE: We identified a novel protumorigenic IL21+ TFH-like cell subset with a CXCR5-PD-1- BTLA-CD69hi tissue-resident phenotype in hepatoma. TLR4-mediated monocyte inflammation and subsequent T-cell STAT1 and STAT3 activation are critical for TFH-like cell induction. TFH-like cells operate via IL21-IFNγ pathways to induce plasma cells and create conditions for M2b macrophage polarization. Cancer Discov; 6(10); 1182-95. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1069.