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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 inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression.

Project description:Low response rate, treatment relapse, and resistance remain key challenges for cancer treatment with immune checkpoint blockade (ICB). Here we report that loss of specific tumor suppressors (TS) 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. Here we identify, by using in vivo CRISPR/Cas9 based loss-of-function screening, that NF1, TSC1, and TGF-β RII as TSs regulating 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 numbers of LAG3+ CD8 and CD4 T cells. ICB targeting LAG3 and PD-L1 simultaneously inhibits metastatic progression in preclinical triple negative breast cancer (TNBC) mouse models of NF1-, TSC1- or TGF-β RII- deficient tumors. Our study thus reveals a role of TSs in regulating metastasis via non-cell-autonomous modulation of the immune compartment and provides proof-of-principle for ICB targeting LAG3 for patients with NF1-, TSC1- or TGF-β RII-inactivated cancers.

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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_vitro]

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 | GSE249971 | GEO

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]

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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]

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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]

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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_vitro]

Project description: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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