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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 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.

SUBMITTER: Wu Z

PROVIDER: S-EPMC10074138 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Wu Zhichong Z Thierry Kevin K Bachy Sophie S Zhang Xinyi X Gamradt Pia P Hernandez-Vargas Hector H Mikaelian Ivan I Tonon Laurie L Pommier Roxanne R Zhao Yajie Y Bertolino Philippe P Hennino Ana A

EMBO reports 20230221 4

We 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 CD45- EPCAM- CD29+ CD106+ CD24+ CD44+ cells. We perform studies with p48-Cre;KrasG12D (KC), pdx1-Cre;KrasG12D ;Ink4a/Arffl/fl (KIC) an ...[more]

PMID: 36802267

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Project description:Inflammation is a physiological state where immune cells evoke a response against detrimental insults. Finding a safe and effective treatment for inflammation associated diseases has been a challenge. In this regard, human mesenchymal stem cells (hMSC), exert immunomodulatory effects and have regenerative capacity making it a promising therapeutic option for resolution of acute and chronic inflammation. T cells play a critical role in inflammation and depending on their phenotype, they can stimulate or suppress inflammatory responses. However, the regulatory effects of hMSC on T cells and the underlying mechanisms are not fully elucidated. Most studies focused on activation, proliferation, and differentiation of T cells. Here, we further investigated memory formation and responsiveness of CD4+ T cells and their dynamics by immune-profiling and cytokine secretion analysis. Umbilical cord mesenchymal stem cells (UC-MSC) were co-cultured with either αCD3/CD28 beads, activated peripheral blood mononuclear cells (PBMC) or magnetically sorted CD4+ T cells. The mechanism of immune modulation of UC-MSC were investigated by comparing different modes of action; transwell, direct cell-cell contact, addition of UC-MSC conditioned medium or blockade of paracrine factor production by UC-MSC. We observed a differential effect of UC-MSC on CD4+ T cell activation and proliferation using PBMC or purified CD4+ T cell co-cultures. UC-MSC skewed the effector memory T cells into a central memory phenotype in both co-culture conditions. This effect on central memory formation was reversible, since UC-MSC primed central memory cells were still responsive after a second encounter with the same stimuli. The presence of both cell-cell contact and paracrine factors were necessary for the most pronounced immunomodulatory effect of UC-MSC on T cells. We found suggestive evidence for a partial role of IL-6 and TGFβ in the UC-MSC derived immunomodulatory function. Collectively, our data show that UC-MSCs clearly affect T cell activation, proliferation and maturation, depending on co-culture conditions for which both cell-cell contact and paracrine factors are needed.

Dataset Information

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

Publications

Pericyte stem cells induce Ly6G<sup>+</sup> cell accumulation and immunotherapy resistance in pancreatic cancer.

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