Go, S.; Demetriou, C.; Hughes, S.; Lanfredini, S.; Valenzano, G.; Ferry, H.; Arbe-Barnes, E.; Sivakumar, S.; Bashford-Rogers, R.; Middleton, M. R.; Mukherjee, S.; Morton, J.; Jones, K.; O'Neill, E.

The immunosuppressive microenvironment in PDAC prevents tumor control but strategies to restore anti-cancer immunology, by increasing CD8 T cell activity, have not been successful. Here we demonstrate how inducing localized physical damage using ionizing radiation (IR) unmasks the benefit of immunotherapy by increasing tissue-resident NK (trNK) cells that support CD8 T activity. Our data confirms that targeting mouse orthotopic PDAC tumors with IR together with CCR5 inhibition and PD1 blockade reduces E-cadherin positive tumor cells by recruiting a hypofunctional NKG2C-ve NK population that supports CD8 T cell involvement. We show an equivalent population in human PDAC cohorts that represents an adaptive-like immunomodulatory trNK-cell that similarly supports CD8 T cell levels in a cDC1-dependent manner. Importantly, a trNK signature associates with survival in PDAC and solid malignancies revealing a potential beneficial role for trNK in improving adaptive anti-tumor responses and supporting CCR5i/PD1 and IR-induced damage as a novel therapeutic approach.