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Senolytic approaches enhance chemotherapy immunogenicity in prostate cancer

ABSTRACT: Cellular senescence is a common outcome of many standard-of-care cytostatic and cytotoxic cancer therapies. Whereas is some contexts therapy-induced senescence can drive tumor growth suppression and anti-tumor immune surveillance through the senescence-associated secretory phenotype (SASP), in others it can promote tumor progression, metastatic dissemination, and immune suppression. How the heterogeneous senescent phenotypes induced by different classes of cancer therapies directly impact tumor and immune responses, and whether understanding those mechanisms could be leveraged for effective combination therapies, has yet to be evaluated in a systematic manner. Here we compared the effects of various CDK inhibitor combinations, chemotherapies, and other DNA damaging agents commonly used in the treatment of advanced prostate cancer on senescence phenotypes in human and mouse prostate tumor models. We observed that while CDK inhibitors could induce senescence in MYC-driven prostate tumor cells, DNA-damaging chemotherapies and Aurora kinase inhibitors mediated a more robust senescence-mediated growth arrest and SASP program, which was paradoxically enhanced in the context of p53 and Rb tumor suppressor losses. The SASP produced by chemotherapy-induced senescence, and in particular with docetaxel, contained not only inflammatory factors that could influence innate immune responses, but also ECM remodeling factors that could facilitate tumor cell dissemination. Though docetaxel treatment could induce senescence and reduce tumor growth in syngeneic prostate cancer mouse models, it was not sufficient to activate anti-tumor immune surveillance or prevent metastatic dissemination. Use of senolytic therapies targeting anti-apoptotic BCL2 and IAP pathways upregulated after docetaxel-induced senescence could effectively clear senescent tumor cells. SMAC mimetic LCL-161 also induced immunogenic cell death capable to remodeling the inflammatory SASP to confer CD8+ T cell activation to further reduce tumor growth and even prevent metastasis in vivo. Our results suggest that combining senescence-inducing chemotherapies with senolytic agents can enhance the immunogenicity and anti-metastatic potential of standard-of-care chemotherapy used for treating prostate cancer patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE316754 | GEO | 2026/01/16

REPOSITORIES: GEO

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Project description:Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Previous observations link the transcription-associated methyltransferase and oncoprotein MLL1 to the DDR, leading us to investigate the role of MLL1 in SASP expression. Our findings reveal direct MLL1 epigenetic control over proproliferative cell cycle genes: MLL1 inhibition represses expression of proproliferative cell cycle regulators required for DNA replication and DDR activation, thus disabling SASP expression. Strikingly, however, these effects of MLL1 inhibition on SASP gene expression do not impair OIS and, furthermore, abolish the ability of the SASP to enhance cancer cell proliferation. More broadly, MLL1 inhibition also reduces Ã¢Â?Â?SASP-likeÃ¢Â?Â? inflammatory gene expression from cancer cells in vitro and in vivo independently of senescence. Taken together, these data demonstrate that MLL1 inhibition may be a powerful and effective strategy for inducing cancerous growth arrest through the direct epigenetic regulation of proliferation-promoting genes and the avoidance of deleterious OIS- or TIS-related tumor secretomes, which can promote both drug resistance and tumor progression. This study examines the genome-wide distribution of gH2A.x and H3K4me3 by chIP-seq, using input and whole histone subunit H3 (respectively) as controls for local sonication efficiency bias. Each of the four chIPs has a single replicate each in (i) IMR90 fibroblasts transfected with a scramble control vector, (ii) the same cells subject to oncogene-induced senescence by stimulation of H-Ras V12, and (iii) in OIS cells with a shRNA targeting MLL1. Additionally, gH2A.x and input were sequenced with another replicate in control and OIS cells (both scramble control).

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Senolytic approaches enhance chemotherapy immunogenicity in prostate cancer

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