Tissue-resident peripheral helper T cells foster hepatocellular carcinoma immune evasion by promoting regulatory B-cell expansion.

Abstract

Background: peripheral helper T (TPH) cells are uniquely positioned within pathologically inflamed non-lymphoid tissues to stimulate B-cell responses and antibody production. However, the phenotype, function, and clinical relevance of TPH cells in hepatocellular carcinoma (HCC) are currently unknown.

Methods: Blood, tumor, and peritumoral liver tissue samples from 39 HCC patients (Sep 2016-Aug 2017) and 101 HCC patients (Sep 2011-Dec 2012) at the Third Affiliated Hospital of Sun Yat-sen University were used. Flow cytometry was used to quantify the expression, phenotype, and function of TPH cells. Log-rank tests were performed to evaluate disease-free survival and overall survival in samples from 39 patients and 101 patients with HCC. TPH cells, CD19+ B cells, and T follicular helper (TFH) cells were cultured separately in vitro or isolated from C57/B6L mice in vivo for functional assays.

Results: TPH cells highly infiltrated tumor tissues, which was correlated with tumor size, early recurrence, and shorter survival time. The tumor-infiltrated TPH cells showed a unique ICOShiCXCL13+IL-21-MAF+BCL-6- phenotype and triggered naïve B-cell differentiation into regulatory B cells. Triggering programmed cell death protein 1 (PD-1) induced the production of CXCL13 by TPH cells, which then suppressed tumor-specific immunity and promoted disease progression.

Conclusion: Our study reveals a novel regulatory mechanism of TPH cell-regulatory B-cell-mediated immunosuppression and provides an important perspective for determining the balance between the differentiation of protumorigenic TPH cells and that of antitumorigenic TFH cells in the HCC microenvironment.