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

Autor:	Go S; Department of Oncology, University of Oxford, Oxford, United Kingdom., Demetriou C; Department of Oncology, University of Oxford, Oxford, United Kingdom., Valenzano G; Department of Oncology, University of Oxford, Oxford, United Kingdom., Hughes S; Department of Oncology, University of Oxford, Oxford, United Kingdom., Lanfredini S; Department of Oncology, University of Oxford, Oxford, United Kingdom., Ferry H; Experimental Medicine Division, University of Oxford, Oxford, United Kingdom., Arbe-Barnes E; University of Oxford Medical School, Oxford, United Kingdom., Sivakumar S; Department of Oncology, University of Oxford, Oxford, United Kingdom., Bashford-Rogers R; Department of Biochemistry, University of Oxford, Oxford, United Kingdom., Middleton MR; Department of Oncology, University of Oxford, Oxford, United Kingdom.; Experimental Medicine Division, University of Oxford, Oxford, United Kingdom.; Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom., Mukherjee S; Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom., Morton J; CRUK Beatson Institute, Glasgow, United Kingdom.; School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom., Jones K; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom., Neill EO; Department of Oncology, University of Oxford, Oxford, United Kingdom.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2024 Dec 10; Vol. 13. Date of Electronic Publication: 2024 Dec 10.
DOI:	10.7554/eLife.92672
Abstrakt:	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. Competing Interests: SG, CD, GV, SH, SL, HF, EA, SS, RB, MM, SM, JM, KJ, EN No competing interests declared (© 2024, Go, Demetriou, Valenzano et al.)
Databáze:	MEDLINE
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