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Senescence defines a distinct subset of myofibroblasts that orchestrates immunosuppression in pancreatic cancer

ABSTRACT: Therapeutic resistance in PDAC is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer associated fibroblasts (CAFs). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAFs) in mouse and human PDAC. These SenCAFs are a subset of myofibroblastic CAFs that localize near tumors ducts, have distinct phenotypes and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we employed a LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Senescence depletion with the KPPC-IA model or with the senolytic drug ABT263/Navitoclax, delayed tumor progression, reduced fibrosis, and relieved immune suppression in macrophages and T lymphocytes. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction.

ORGANISM(S): Homo sapiens

PROVIDER: GSE255978 | GEO | 2024/06/21

REPOSITORIES: GEO

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Senescence defines a distinct subset of myofibroblasts that orchestrates immunosuppression in pancreatic cancer

Project description:Therapeutic resistance in PDAC is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer associated fibroblasts (CAFs). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAFs) in mouse and human PDAC. These SenCAFs are a subset of myofibroblastic CAFs that localize near tumors ducts, have distinct phenotypes and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we employed a LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Senescence depletion with the KPPC-IA model or with the senolytic drug ABT263/Navitoclax, delayed tumor progression, reduced fibrosis, and relieved immune suppression in macrophages and T lymphocytes. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction.

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Differential Activity of MAPK signalling Defines Fibroblast Subtypes in Pancreatic Cancer (scRNA-Seq)

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Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma impair CD8+ T cell activation and limit responsiveness to immunotherapy in mice

Project description:Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions, yet the potential for targeting such senescent cells for improved therapy remains largely unknown. Here, we uncover the presence of a senescent subset of cancer-associated fibroblasts (CAFs) within pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs represented different previously-defined CAF subtypes. Senescent CAFs isolated from mouse and humans expressed elevated levels of immunoregulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8+ T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8+ T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.

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Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma suppress CD8+ T cell activation and inhibit response to immune checkpoint therapy [Cultured_Human_Mouse]

Project description:Senescent cells appear within tumors and their stroma, exerting complex pro- and anti-tumorigenic functions. The effects of senescent tumor stromal cells are mostly unknown, as is the potential for targeting such senescent cells for improved therapy. Here we uncover the presence of a senescent subset of cancer-associated fibroblasts (CAFs) within pancreatic adenocarcinomas and in premalignant pancreatic lesions. Senescent CAFs show reduced proliferation, and are often associated with the inflammatory CAF (iCAF) subtype. We isolated and characterized senescent CAFs from mouse models and directly from human patients, and found that they express elevated levels of immune-regulatory genes. In a panel of mouse PDACs, high levels of senescent CAFs correlated with low T cell infiltration. Removal of senescent CAFs from PDAC stroma, either genetically or through treatment with the senolytic drug ABT-199 (venetoclax), a Bcl2 inhibitor, increased rates of activated cytotoxic CD8+ T cells within tumors. Conversely, activation of CAF senescence within PDACs led to reduced CD8+ T cell numbers. Media from senescent PDAC CAFs inhibited T cell proliferation and activation. We show that implanted PDAC tumors show improved response to immune checkpoint therapy when co-treated with the senolytic drug. These results reveal that the presence of senescent CAFs in PDAC stroma acts to repress cytotoxic T cell activity, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.

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Single-Cell Analysis of Human Pancreatic Ductal Adenocarcinoma

Project description:<p>Cancer-associated fibroblasts (CAFs) are major players in the progression and drug resistance of pancreatic ductal adenocarcinoma (PDAC). CAFs constitute a diverse cell population consisting of several recently described subtypes, although the extent of CAF heterogeneity has remained undefined. Here we employ single-cell RNA-sequencing to thoroughly characterize the neoplastic and tumor microenvironment content of human PDAC tumors. Six human PDAC tumor specimens from six patients were collected, and processed for single-cell RNA-sequencing analysis. Adjacent-normal pancreas tissue was also collected from two of the patients. Tumor samples were digested, and fluorescence-activated cell sorting was used to isolate viable cells. For one tumor sample, viable, CD45-negative, CD31-negative, and EpCAM-negative cells were also isolated to enrich for CAFs. The 10X Chromium platform was then used to isolate single cells for RNA-sequencing analysis. This work has demonstrated the differences in immune cell populations between adjacent-normal and tumor tissues, and identified subpopulations of epithelial cells and CAFs present in PDAC tumors. This high-throughput analysis is a resource to better understand the cell populations present in PDAC, and may ultimately aid in the development of more effective therapies for this deadly malignancy.</p>

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