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EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance [RNA-seq]

ABSTRACT: Immunotherapies that produce durable responses in some malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to rampant immune suppression and poor tumor immunogenicity. We and others have demonstrated that induction of the senescence-associated secretory phenotype (SASP) can be an effective approach to activate anti-tumor Natural Killer (NK) and T cell immunity. Here we found the pancreas tumor microenvironment (TME) suppresses NK and T cell surveillance following therapy-induced senescence through EZH2-mediated epigenetic repression of pro-inflammatory SASP genes. EZH2 blockade stimulated production of SASP chemokines CCL2 and CXCL9/10, leading to enhanced NK and T cell infiltration and PDAC eradication in mouse models. EZH2 activity was also associated with suppression of chemokine signaling and cytotoxic lymphocytes and reduced survival in PDAC patients. These results demonstrate that EZH2 represses of the pro-inflammatory SASP, and that EZH2 inhibition combined with senescence-inducing therapy could be a powerful means to achieve immune-mediated tumor control in PDAC.

ORGANISM(S): Mus musculus

PROVIDER: GSE203621 | GEO | 2023/03/14

REPOSITORIES: GEO

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EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance

Project description:Immunotherapies that produce durable responses in some malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to rampant immune suppression and poor tumor immunogenicity. We and others have demonstrated that induction of the senescence-associated secretory phenotype (SASP) can be an effective approach to activate anti-tumor Natural Killer (NK) and T cell immunity. Here we found the pancreas tumor microenvironment (TME) suppresses NK and T cell surveillance following therapy-induced senescence through EZH2-mediated epigenetic repression of pro-inflammatory SASP genes. EZH2 blockade stimulated production of SASP chemokines CCL2 and CXCL9/10, leading to enhanced NK and T cell infiltration and PDAC eradication in mouse models. EZH2 activity was also associated with suppression of chemokine signaling and cytotoxic lymphocytes and reduced survival in PDAC patients. These results demonstrate that EZH2 represses of the pro-inflammatory SASP, and that EZH2 inhibition combined with senescence-inducing therapy could be a powerful means to achieve immune-mediated tumor control in PDAC.

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EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance [CUT&Tag]

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Bulk-RNA seq in PC3shTIMP cell treated with Vehicle, Docetaxel , Adapelene or their combination (Combo)

Project description:Cellular senescence, a stable cell growth arrest, can have dual effects in tumors, either suppressing or promoting tumor progression. The Senescence-Associated Secretory Phenotype (SASP), released by senescent cells, plays a crucial role in this dichotomy. Consequently, the clinical challenge lies in developing therapies that safely enhance senescence in cancer, promoting tumor-suppressive over tumor-promoting SASP factors. Here, we identified the Retinoic-Acid-Receptor (RAR) agonist Adapalene as an effective pro-senescence compound in prostate cancer (PCa). The reactivation of the RARs triggers a strong senescence response and a tumor-suppressive SASP. In preclinical mouse models of PCa, the combination of Adapalene and Docetaxel, promotes a tumor-suppressive SASP that activates NK cell-mediated tumor clearance more effectively than either agent alone. This approach increases the efficacy of allogenic infusion of human NK cells in mice injected with human PCa cells, suggesting an alternative therapeutic strategy to stimulate the anti-tumor immune response in "immunologically cold" tumors.

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Whole genome expression data comparison between WT and Cebpg-/- MEFs.

Project description:C/EBPÎ² is an important regulator of oncogene-induced senescence (OIS). Here we show that C/EBPÎ³, a heterodimeric partner of C/EBPÎ² whose biological functions are not well understood, inhibits cellular senescence. Cebpg-/- MEFs proliferated poorly, entered senescence prematurely, and expressed a pro-inflammatory gene signature, including elevated levels of senescence-associated secretory phenotype (SASP) genes whose induction by oncogenic stress requires C/EBPÎ². The senescence-suppressing activity of C/EBPÎ³ required its ability to heterodimerize with C/EBPÎ². Covalently linked C/EBPÎ² homodimers (Î²~Î²) inhibited the proliferation and tumorigenicity of RasV12-transformed NIH3T3 cells, activated SASP gene expression, and recruited the CBP co-activator in a Ras-dependent manner, whereas Î³~Î² heterodimers lacked these capabilities and efficiently rescued proliferation of Cebpg-/- MEFs. C/EBPÎ² depletion partially restored growth of C/EBPÎ³-deficient cells, indicating that the increased levels of C/EBPÎ² homodimers in Cebpg-/- MEFs inhibit proliferation. The proliferative functions of C/EBPÎ³ are not restricted to fibroblasts, as hematopoietic progenitors from Cebpg-/- bone marrow also displayed impaired growth. Furthermore, high CEBPG expression correlated with poorer clinical prognoses in several human cancers, and C/EBPÎ³ depletion decreased proliferation and induced senescence in lung tumor cells. Our findings demonstrate that C/EBPÎ³ neutralizes the cytostatic activity of C/EBPÎ² through heterodimerization, which prevents senescence and suppresses basal transcription of SASP genes. Mouse embryonic fibroblasts were isolated at E13.5 and propagated. At passage 3 cells were plated with equal density and collected 48 hours later.

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