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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.

| S-EPMC11245525 | biostudies-literature

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 [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_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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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]

| PRJNA1051525 | ENA

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Project description:Critical immune-suppressive pathways beyond programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) require greater attention. Nectins and nectin-like molecules might be promising targets for immunotherapy, since they play critical roles in cell proliferation and migration and exert immunomodulatory functions in pathophysiological conditions. Here, we show CD155 expression in both malignant cells and tumor-infiltrating myeloid cells in humans and mice. Cd155-/- mice displayed reduced tumor growth and metastasis via DNAM-1 upregulation and enhanced effector function of CD8+ T and NK cells, respectively. CD155-deleted tumor cells also displayed slower tumor growth and reduced metastases, demonstrating the importance of a tumor-intrinsic role of CD155. CD155 absence on host and tumor cells exerted an even greater inhibition of tumor growth and metastasis. Blockade of PD-1 or both PD-1 and CTLA4 was more effective in settings in which CD155 was limiting, suggesting the clinical potential of cotargeting PD-L1 and CD155 function.

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