Innate ?? T Cells Mediate Antitumor Immunity by Orchestrating Immunogenic Macrophage Programming.

ABSTRACT: Unconventional T-lymphocyte populations are emerging as important regulators of tumor immunity. Despite this, the role of TCR??+CD4-CD8-NK1.1- innate ?? T cells (i??T) in pancreatic ductal adenocarcinoma (PDA) has not been explored. We found that i??Ts represent ?10% of T lymphocytes infiltrating PDA in mice and humans. Intratumoral i??Ts express a distinct T-cell receptor repertoire and profoundly immunogenic phenotype compared with their peripheral counterparts and conventional lymphocytes. i??Ts comprised ?75% of the total intratumoral IL17+ cells. Moreover, i??T-cell adoptive transfer is protective in both murine models of PDA and human organotypic systems. We show that i??T cells induce a CCR5-dependent immunogenic macrophage reprogramming, thereby enabling marked CD4+ and CD8+ T-cell expansion/activation and tumor protection. Collectively, i??Ts govern fundamental intratumoral cross-talk between innate and adaptive immune populations and are attractive therapeutic targets. SIGNIFICANCE: We found that i??Ts are a profoundly activated T-cell subset in PDA that slow tumor growth in murine and human models of disease. i??Ts induce a CCR5-dependent immunogenic tumor-associated macrophage program, T-cell activation and expansion, and should be considered as novel targets for immunotherapy.See related commentary by Banerjee et al., p. 1164.This article is highlighted in the In This Issue feature, p. 1143.

SUBMITTER: Hundeyin M 

PROVIDER: S-EPMC6726581 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature