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The efficacy of chemotherapy is limited by intratumoral senescent cells that persist through the upregulation of PD-L2

ABSTRACT: The efficacy of chemotherapy is limited by intratumoral senescent cells that persist through the upregulation of PD-L2

PROVIDER: PRJNA865285 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20751608.fastq.gz	Fastqsanger.gz
	SRR20751609.fastq.gz	Fastqsanger.gz
	SRR20751610.fastq.gz	Fastqsanger.gz
	SRR20751611.fastq.gz	Fastqsanger.gz
	SRR20751612.fastq.gz	Fastqsanger.gz

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The efficacy of chemotherapy is limited by intratumoral senescent cells that persist through the upregulation of PD-L2

Project description:Anti-cancer therapies often result in a subset of surviving cancer cells that undergo therapy induced senescence (TIS). Senescent cancer cells strongly modify the intratumoral microenvironment favoring immunosuppression and, thereby, tumor growth. An emerging strategy to optimise current therapies is to combine them with treatments that eliminate senescent cells. To this end, we undertook an unbiased proteomics approach to identify surface markers contributing to senescent cells immune evasion. Through this approach, we discovered that the immune checkpoint inhibitor PD-L2, but not PD-L1, is upregulated across multiple senescent human and murine cells. Importantly, blockade of PD-L2 strongly synergises with genotoxic chemotherapy, causing remission of solid tumors in mice. We show that PD-L2 inhibition prevents the persistence of chemotherapy-induced senescent cells, which exert cell-extrinsic immunomodulatory actions. In particular, upon chemotherapy, tumors deficient in PD-L2 fail to produce cytokines of the CXCL family, do not recruit myeloid-derived suppressor cells (MDSCs) and are eliminated in a CD8 T cell-dependent manner. We conclude that blockade of PD-L2 improves chemotherapy efficacy by reducing the intratumoral burden of senescent cells and their associated recruitment of immunosuppressive cells. These findings provide a novel strategy to exploit vulnerabilities arising in tumor cells as a result of therapy-induced damage and cellular senescence

2022-10-19 | GSE210334 | GEO

The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2.

Project description:Chemotherapy often generates intratumoral senescent cancer cells that strongly modify the tumor microenvironment, favoring immunosuppression and tumor growth. We discovered, through an unbiased proteomics screen, that the immune checkpoint inhibitor programmed cell death 1 ligand 2 (PD-L2) is highly upregulated upon induction of senescence in different types of cancer cells. PD-L2 is not required for cells to undergo senescence, but it is critical for senescent cells to evade the immune system and persist intratumorally. Indeed, after chemotherapy, PD-L2-deficient senescent cancer cells are rapidly eliminated and tumors do not produce the senescence-associated chemokines CXCL1 and CXCL2. Accordingly, PD-L2-deficient pancreatic tumors fail to recruit myeloid-derived suppressor cells and undergo regression driven by CD8 T cells after chemotherapy. Finally, antibody-mediated blockade of PD-L2 strongly synergizes with chemotherapy causing remission of mammary tumors in mice. The combination of chemotherapy with anti-PD-L2 provides a therapeutic strategy that exploits vulnerabilities arising from therapy-induced senescence.

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Intratumoral heterogeneity of prostate cancers

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