Journal Article

Tissue-resident natural killer cells support survival in pancreatic cancer through promotion of cDC1-CD8 T activity

Jones, Keaton, Morton, Jennifer, Lanfredini, Simone, Bashford-Rogers, Rachel, Neill, Eric O, Mukherjee, Somnath, Hughes, Sophie, Sivakumar, Shivan, Arbe-Barnes, Edward, Demetriou, Constantinos, Go, Simei, Valenzano, Giampiero, Ferry, Helen, Middleton, Mark R

2024

Overview

The immunosuppressive microenvironment in pancreatic ductal adenocarcinoma (PDAC) prevents tumor control and strategies to restore anti-cancer immunity (i.e. by increasing CD8 T-cell activity) have had limited success. Here, we demonstrate how inducing localized physical damage using ionizing radiation (IR) unmasks the benefit of immunotherapy by increasing tissue-resident natural killer (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 hypoactive NKG2D -ve NK population, phenotypically reminiscent of trNK cells, that supports CD8 T-cell involvement. We show an equivalent population in human single-cell RNA sequencing (scRNA-seq) PDAC cohorts that represents immunomodulatory trNK cells that could similarly support CD8 T-cell levels in a cDC1-dependent manner. Importantly, a trNK signature associates with survival in PDAC and other solid malignancies revealing a potential beneficial role for trNK in improving adaptive anti-tumor responses and supporting CCR5 inhibitor (CCR5i)/αPD1 and IR-induced damage as a novel therapeutic approach.

• Publisher: eLife Sciences Publications, Ltd,eLife Sciences Publications Ltd
• Subject: Animals / Cancer Biology / Carcinoma, Pancreatic Ductal - immunology / Carcinoma, Pancreatic Ductal - pathology / Carcinoma, Pancreatic Ductal - therapy / CD8-Positive T-Lymphocytes - immunology / Cell Line, Tumor / Humans / immune / Immunology and Inflammation / Immunotherapy - methods / Killer Cells, Natural - immunology / KPC / Mice / Mice, Inbred C57BL / NK Cell Lectin-Like Receptor Subfamily K - genetics / NK Cell Lectin-Like Receptor Subfamily K - metabolism / NK cells / pancreatic / Pancreatic Neoplasms - immunology / Pancreatic Neoplasms - pathology / Pancreatic Neoplasms - therapy / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Programmed Cell Death 1 Receptor - metabolism / Receptors, CCR5 - genetics / Receptors, CCR5 - metabolism / tissue resident / Tumor Microenvironment - immunology