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

ABSTRACT: We report the identification of a cell population that shares pericyte, stromal and stemness features, does not harbour the KrasG12D 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;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 co-injection 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 co-injected 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.

SUBMITTER: Dr. Zhichong Wu

PROVIDER: S-SCDT-10_15252-EMBR_202256524 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:The repeated treatment of cancer cells with chemo- or radiotherapy induces therapy resistance, but it was previously unknown whether the same effect occurs upon continuous exposure of cancer cells to diet-derived chemopreventive agents. We elucidated this interesting question in pancreatic ductal adenocarcinoma, which is a highly aggressive cancer entity with a marked resistance toward gemcitabine and other cytotoxic drugs. The isothiocyanate sulforaphane, present in cruciferous vegetables, and the polyphenol quercetin, present in many fruits and vegetables induced apoptosis and reduced viability in gemcitabine-sensitive BxPC-3 cells but not in non-malignant ductal pancreas cells and mesenchymal stromal cells. In turn, BxPC-3 cells were treated with increasing concentrations of gemcitabine, sulforaphane or quercetin for more than 1 year and the surviving subclones Bx-GEM, Bx-SF and Bx-Q were selected, respectively. While Bx-GEM cells acquired a total resistance, Bx-SF or Bx-Q cells largely kept their sensitivity as proved by MTT assay, annexin staining and FACS analysis. The evaluation of the self-renewal-, differentiation- and migration-potential by colony formation, differentiation or migration assays demonstrated that cancer stem cell features were enriched in gemcitabine-resistant cells, but decreased in sulforaphane- and quercetin-long time-treated cells. These results were confirmed by orthotopic xenotransplantation of cancer cells to the mouse pancreas, where Bx-GEM formed large, Bx-Q small and Bx-SF cells almost undetectable tumors. An mRNA expression profiling array and subsequent gene set enrichment analysis and qRT-PCR confirmed that tumor progression markers were enriched in Bx-GEM, but reduced in Bx-SF and Bx-Q cells. This study demonstrates that the continuous exposure of pancreatic cancer cells to sulforaphane or quercetin does not induce resistance in surviving cells but reduces tumorigenicity by inhibition of tumor progression markers. These results highlight that cancer cells may not adapt to the preventive and therapeutic effects of a regular fruit- and vegetable-based diet.

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

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