Intratumoral Foxp3+RORγt+ T cell infiltration determines poor prognosis and immunoevasive contexture in gastric cancer patients

Abstract

Background: Foxp3⁺RORγt⁺ T cells possess both characteristics of regulatory T cells and T helper 17 cells and show significant immunoregulatory functions in autoimmune diseases. However, the role and clinical significance of Foxp3⁺RORγt⁺ T cells in gastric cancer remains unclear.

Methods: We enrolled 452 gastric cancer tissue microarray samples and 60 fresh tumor tissue samples from Zhongshan Hospital. The infiltration of Foxp3⁺RORγt⁺ T cells and immune contexture were examined by immunohistochemistry and flow cytometry. Survival analyses of patient subgroups were conducted by Kaplan-Meier curves, log-rank test and Cox proportional model.

Results: High infiltration of Foxp3⁺RORγt⁺ T cells predicted poor overall survival (P = 0.0222 and 0.0110) and inferior therapeutic response (P = 0.003 for interaction) in gastric cancer. Foxp3⁺RORγt⁺ T cells were associated with impaired effective function of CD8⁺ T cells featured by decreased interferon-γ, granzyme B and CD107a expression. Co-evaluation of Foxp3⁺RORγt⁺ T cells and CD8⁺ T cells could predict survival outcomes and chemotherapeutic responsiveness more precisely.

Conclusions: We found that Foxp3⁺RORγt⁺ T cells could potentially attenuate effective functions of CD8⁺ T cells and led to adverse survival outcomes and inferior chemotherapeutic responsiveness. Moreover, the novel co-evaluation system might be useful for prognosis prediction for appropriate treatment in gastric cancer.

Novelty and impact statements: Clinical significance of Foxp3⁺RORγts⁺ T cells has not been studied in gastric cancer. Herein, we investigated the prognostic value of Foxp3+RORγt+ T cells in 452 patients. We demonstrated that intratumoral Foxp3⁺RORγt⁺ T cell infiltration was a prognostic biomarker for overall survival and the identification of patients might benefit from post-gastrectomy 5-fluorouracil. These findings allow a more precise stratification upon the co-evaluation with CD8⁺ T cells to better clinical management for patients who would benefit from 5-fluorouracil.

Keywords: Adjuvant chemotherapy; Chemotherapeutic responsiveness; Foxp3+RORγt+ T cells; Gastric cancer; Prognosis.