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Temporal genomic analysis of melanoma rejection identifies regulators of tumor immune evasion

ABSTRACT: Temporal genomic analysis of melanoma rejection identifies regulators of tumor immune evasion

PROVIDER: PRJNA1036166 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26687666_1.fastq.gz	Fastqsanger.gz
	SRR26687666_2.fastq.gz	Fastqsanger.gz
	SRR26687667_1.fastq.gz	Fastqsanger.gz
	SRR26687667_2.fastq.gz	Fastqsanger.gz
	SRR26687668_1.fastq.gz	Fastqsanger.gz

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Temporal genomic analysis of melanoma rejection identifies regulators of tumor immune evasion [scc35]

Project description:Temporal genomic analysis of melanoma rejection identifies regulators of tumor immune evasion [scc35]

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Temporal genomic analysis of melanoma rejection identifies regulators of tumor immune evasion [scc]

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Temporal genomic analysis of melanoma rejection identifies regulators of tumor immune evasion.

Project description:Decreased intra-tumor heterogeneity (ITH) correlates with increased patient survival and immunotherapy response. However, even highly homogenous tumors may display variability in their aggressiveness, and how immunologic-factors impinge on their aggressiveness remains understudied. Here we studied the mechanisms responsible for the immune-escape of murine tumors with low ITH. We compared the temporal growth of homogeneous, genetically-similar single-cell clones that are rejected vs. those that are not-rejected after transplantation in-vivo using single-cell RNA sequencing and immunophenotyping. Non-rejected clones showed high infiltration of tumor-associated-macrophages (TAMs), lower T-cell infiltration, and increased T-cell exhaustion compared to rejected clones. Comparative analysis of rejection-associated gene expression programs, combined with in-vivo CRISPR knockout screens of candidate mediators, identified Mif (macrophage migration inhibitory factor) as a regulator of immune rejection. Mif knockout led to smaller tumors and reversed non-rejection-associated immune composition, particularly, leading to the reduction of immunosuppressive macrophage infiltration. Finally, we validated these results in melanoma patient data.

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Temporal genomic analysis of melanoma rejection identifies regulators of tumor immune evasion [scc]

Project description:Decreased intra-tumor heterogeneity (ITH) correlates with increased patient survival and immunotherapy response. However, the mechanism underlying this association remains inconclusive since additional factors dictate tumor aggressiveness. Here, we study the mechanisms responsible for the immune escape of tumors bearing low ITH. We compare homogeneous, genetically similar single-cell clones that are rejected vs. non-rejected after transplantation. We followed the growth of these clone-derived tumors over time using single-cell RNA sequencing and immunophenotyping. Non-rejected clones show high infiltration of tumor-associated macrophages (TAM), increased Mif expression, lower T-cell infiltration, and increased T-cell exhaustion. Mif KO led to smaller tumors and reversed these immune phenotypes, validating its role in the growth of low ITH tumors. Mif secretion by these tumor cells causes TAM infiltration, thus contributing to an immunosuppressive environment that supports aggressive growth. We validated this result in melanoma patient data, confirming that high levels of MIF distinguish aggressive from non-aggressive ITHs.

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Temporal genomic analysis of melanoma rejection identifies regulators of tumor immune evasion [scc35]

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Temporal genomic analysis of melanoma rejection identifies regulators of tumor immune evasion

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-12-12 | GSE247059 | GEO

E3 ubiquitin ligase HECTD2 mediates melanoma progression and immune evasion

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Project description:Genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection. However, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 relieves endogenous DNA damage and suppresses cGAS-STING-dependent signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a transcriptional regulatory element in the PD-L1 gene, thereby promoting PD-L1 expression in cancer cells. SMARCAL1 loss hinders the ability of tumor cells to induce PD-L1 in response to genomic instability, enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncover SMARCAL1 as a promising target for cancer immunotherapy.

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