γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation

Inflammation is paramount in pancreatic oncogenesis. We identified a uniquely activated gamma delta T cell population, which constituted similar to 40% of tumor-infiltrating T cells in human pancreatic ductal adenocarcinoma (PDA). Recruitment and activation of gamma delta T cells was contingent on diverse chemokine signals. Deletion, depletion, or blockade of gamma delta T cell recruitment was protective against PDA and resulted in increased infiltration, activation, and Th1 polarization of alpha beta T cells. Although alpha beta T cells were dispensable to outcome in PDA, they became indispensable mediators of tumor protection upon gamma delta T cell ablation. PDAinfiltrating gamma delta T cells expressed high levels of exhaustion ligands and thereby negated adaptive anti-tumor immunity. Blockade of PD-L1 in gamma delta T cells enhanced CD4(+) and CD8(+) T cell infiltration and immunogenicity and induced tumor protection suggesting that gamma delta T cells are critical sources of immune-suppressive checkpoint ligands in PDA. We describe gamma delta T cells as central regulators of effector T cell activation in cancer via novel cross-talk.