Innate αβ T cells Mediate Antitumor Immunity by Orchestrating Immunogenic Macrophage Programming.

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