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

Journal article

<jats:p>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<jats:sup>-ve</jats:sup> 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.</jats:p>

Authors: Go, S; Demetriou, C; Valenzano, G; Hughes, S; Lanfredini, S

• Publication status: Published
• Publisher: eLife Sciences Publications
• Journal: eLife
• Volume: 13
• Article number: RP92672
• Publication date: 2024-12-10
• DOI: 10.7554/elife.92672.3
• EISSN: 2050-084X
• Language: English
• Keywords: 3204 Immunology; 5.1 Pharmaceuticals; Pancreatic Cancer; Cancer; 3211 Oncology and Carcinogenesis; Immunotherapy; Orphan Drug; 5.2 Cellular and gene therapies; 32 Biomedical and Clinical Sciences; Digestive Diseases; 3 Good Health and Well Being; Rare Diseases; 2.1 Biological and endogenous factors