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

We report the identification of a cell population that shares pericyte, stromal and stemness features, does not harbor the Kras G12D mutation and drives tumoral growth in vitro and in vivo . We term these cells pericyte stem cells (PeSCs) and define them as CD45 − EPCAM − CD29 + CD106 + CD24 + CD44 + cells. We perform studies with p48 ‐Cre; Kras G12D (KC), pdx1 ‐Cre; Kras G12D ; Ink4a / Arf fl/fl (KIC) and pdx1 ‐Cre; Kras G12D ; p53 R172H (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. Synopsis Pericyte stem cells (PeSCs) represent a newly identified cell population that shares pericyte, stromal and stemness features and drives tumoral growth in pancreatic cancer. This study reports on the role of these cells within the tumor microenvironment. PeSCs are barely detectable in the pancreas under steady‐state conditions. PeSC are present in the neoplastic microenvironment in pancreatic cancer both in humans and mice. Co‐injection of PeSCs and tumor epithelial cells increases the differentiation of Ly6G + myeloid‐derived suppressor cells. PeSCs instruct immunosuppressive myeloid cell responses to bypass PD‐1 targeting. Graphical Abstract Pericyte stem cells (PeSCs) represent a newly identified cell population that shares pericyte, stromal and stemness features and drives tumoral growth in pancreatic cancer. This study reports on the role of these cells within the tumor microenvironment.