Pericyte stem cells induce Ly6G+ cell accumulation and immunotherapy resistance in pancreatic cancer

Author:

Wu Zhichong1234ORCID,Thierry Kevin123ORCID,Bachy Sophie123,Zhang Xinyi123,Gamradt Pia123,Hernandez‐Vargas Hector123ORCID,Mikaelian Ivan123,Tonon Laurie123,Pommier Roxanne123,Zhao Yajie1235,Bertolino Philippe123ORCID,Hennino Ana123ORCID

Affiliation:

1. Cancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286 Lyon France

2. Université Lyon 1 Lyon France

3. Centre Léon Bérard Lyon France

4. Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai China

5. Department of Geriatrics, Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai China

Abstract

AbstractWe report the identification of a cell population that shares pericyte, stromal and stemness features, does not harbor the KrasG12D mutation and drives tumoral growth in vitro and in vivo. We term these cells pericyte stem cells (PeSCs) and define them as CD45EPCAMCD29+CD106+CD24+CD44+ cells. We perform studies with p48‐Cre;KrasG12D (KC), pdx1‐Cre;KrasG12D;Ink4a/Arffl/fl (KIC) and pdx1‐Cre;KrasG12D;p53R172H (KPC) and tumor tissues from PDAC and chronic pancreatitis patients. We also perform single‐cell RNAseq analysis and reveal a unique signature of PeSC. Under steady‐state conditions, PeSCs are barely detectable in the pancreas but present in the neoplastic microenvironment both in humans and mice. The coinjection of PeSCs and tumor epithelial cells leads to increased tumor growth, differentiation of Ly6G+ myeloid‐derived suppressor cells, and a decreased amount of F4/80+ macrophages and CD11c+ dendritic cells. This population induces resistance to anti‐PD‐1 immunotherapy when coinjected with epithelial tumor cells. Our data reveal the existence of a cell population that instructs immunosuppressive myeloid cell responses to bypass PD‐1 targeting and thus suggest potential new approaches for overcoming resistance to immunotherapy in clinical settings.

Funder

Fondation de France

CNIB

Inserm Transfert

Publisher

Springer Science and Business Media LLC

Subject

Genetics,Molecular Biology,Biochemistry

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