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

Abstract

The existence, regulation, and functions of IL21⁺ immune cells are poorly defined in human cancers. Here, we identified a subset of protumorigenic IL21⁺ T_FH-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 T_FH cells present in lymph nodes. However, these T_FH-like cells displayed a unique CXCR5^-PD-1^lo/-BTLA^-CD69^hi tissue-resident phenotype with substantial IFNγ production, which differed from the phenotype of T_FH cells. Toll-like receptor 4 (TLR4)-elicited innate monocyte inflammation was important for IL21⁺ T_FH-like cell induction in tumors, and activation of STAT1 and STAT3 was critical for T_FH-like cell polarization in this process. Importantly, the T_FH-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 T_FH-like cells links innate inflammation to immune privilege in tumors.

Significance: We identified a novel protumorigenic IL21⁺ T_FH-like cell subset with a CXCR5^-PD-1^- BTLA^-CD69^hi tissue-resident phenotype in hepatoma. TLR4-mediated monocyte inflammation and subsequent T-cell STAT1 and STAT3 activation are critical for T_FH-like cell induction. T_FH-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.