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Loss of tumor suppressors promotes a non-cell-autonomous inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE249972 | GEO | 2024/03/01

REPOSITORIES: GEO

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Loss of tumor suppressors promotes a non-cell-autonomous inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression [ATAC_seq]

Project description:Low response rate, treatment relapse, and resistance remain key challenges in the application of immune checkpoint blockade (ICB). Here we report that loss of specific tumor suppressors (TSs) induces an inflammatory response and promotes an immune suppressive tumor microenvironment. Importantly, low expression of these TSs is associated with a higher expression of immune checkpoint inhibitory mediators. Using CRIPSR/Cas9 in vivo loss-of-function screening, we identified NF1, TSC1, and TGF-b RII as TSs that regulate immune composition. Loss of each of these three TSs leads to alterations in chromatin accessibility and enhances IL6-JAK3-STAT3/6 inflammatory pathways. This results in an immune suppressive landscape characterized by increased LAG3+ CD8 and CD4 T cells. ICB targeting LAG3 in combination with PD-L1 decreased metastatic progression in preclinical triple negative breast cancer (TNBC) mouse models of NF1-, TSC1- or TGF-b RII- deficient tumors. Together, our studies identify LAG3 as a new ICB target for patients whose cancer displays inactivation of these TSs. In addition, our studies reveal an unexpected role for TSs in the regulation of metastatic spread via non-cell-autonomous modulation of the immune compartment.

2024-03-01 | GSE249967 | GEO

Loss of tumor suppressors promotes a non-cell-autonomous inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression [RNA_seq_vitro]

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Loss of tumor suppressors promotes a non-cell-autonomous inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression [RNA_seq_Cas9_PT]

2024-03-01 | GSE249969 | GEO

Loss of tumor suppressors promotes a non-cell-autonomous inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression

Project description:Loss of tumor suppressors promotes a non-cell-autonomous inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression

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Loss of tumor suppressors promotes a non-cell-autonomous inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression [RNA_seq_Cas9_PT]

Project description:Loss of tumor suppressors promotes a non-cell-autonomous inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression [RNA_seq_Cas9_PT]

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Loss of tumor suppressors promotes a non-cell-autonomous inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression [ATAC_seq]

Project description:Loss of tumor suppressors promotes a non-cell-autonomous inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression [ATAC_seq]

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Non-cell-autonomous tumor suppression by p53.

Project description:The p53 tumor suppressor can restrict malignant transformation by triggering cell-autonomous programs of cell-cycle arrest or apoptosis. p53 also promotes cellular senescence, a tumor-suppressive program that involves stable cell-cycle arrest and secretion of factors that modify the tissue microenvironment. In the presence of chronic liver damage, we show that ablation of a p53-dependent senescence program in hepatic stellate cells increases liver fibrosis and cirrhosis associated with reduced survival and enhances the transformation of adjacent epithelial cells into hepatocellular carcinoma. p53-expressing senescent stellate cells release factors that skew macrophage polarization toward a tumor-inhibiting M1-state capable of attacking senescent cells in culture, whereas proliferating p53-deficient stellate cells secrete factors that stimulate polarization of macrophages into a tumor-promoting M2-state and enhance the proliferation of premalignant cells. Hence, p53 can act non-cell autonomously to suppress tumorigenesis by promoting an antitumor microenvironment, in part, through secreted factors that modulate macrophage function.

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Local Activation of p53 in the Tumor Microenvironment Overcomes Immune Suppression and Enhances Antitumor Immunity.

Project description:Mutations in tumor suppressor p53 remain a vital mechanism of tumor escape from apoptosis and senescence. Emerging evidence suggests that p53 dysfunction also fuels inflammation and supports tumor immune evasion, thereby serving as an immunological driver of tumorigenesis. Therefore, targeting p53 in the tumor microenvironment (TME) also represents an immunologically desirable strategy for reversing immunosuppression and enhancing antitumor immunity. Using a pharmacological p53 activator nutlin-3a, we show that local p53 activation in TME comprising overt tumor-infiltrating leukocytes (TILeus) induces systemic antitumor immunity and tumor regression, but not in TME with scarce TILeus, such as B16 melanoma. Maneuvers that recruit leukocytes to TME, such as TLR3 ligand in B16 tumors, greatly enhanced nutlin-induced antitumor immunity and tumor control. Mechanistically, nutlin-3a-induced antitumor immunity was contingent on two nonredundant but immunologically synergistic p53-dependent processes: reversal of immunosuppression in the TME and induction of tumor immunogenic cell death, leading to activation and expansion of polyfunctional CD8 CTLs and tumor regression. Our study demonstrates that unlike conventional tumoricidal therapies, which rely on effective p53 targeting in each tumor cell and often associate with systemic toxicity, this immune-based strategy requires only limited local p53 activation to alter the immune landscape of TME and subsequently amplify immune response to systemic antitumor immunity. Hence, targeting the p53 pathway in TME can be exploited to reverse immunosuppression and augment therapeutic benefits beyond tumoricidal effects to harness tumor-specific, durable, and systemic antitumor immunity with minimal toxicity. Cancer Res; 77(9); 2292-305. ©2017 AACR.

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