Innate αβ T Cells Mediate Antitumor Immunity by Orchestrating Immunogenic Macrophage Programming

Abstract

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