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

Chibaya, Loretah, Murphy, Katherine C, DeMarco, Kelly D, Gopalan, Sneha, Liu, Haibo, Parikh, Chaitanya N, Lopez-Diaz, Yvette, Faulkner, Melissa, Li, Junhui, Morris, John P, Ho, Yu-Jui, Chana, Sachliv K, Simon, Janelle, Luan, Wei, Kulick, Amanda, de Stanchina, Elisa, Simin, Karl, Zhu, Lihua Julie, Fazzio, Thomas G, Lowe, Scott W, Ruscetti, Marcus (June 2023) EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance. Nature Cancer, 4 (6). pp. 872-892. ISSN 2662-1347

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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) cell and T cell immunity. In the present study, we found that the pancreas tumor microenvironment suppresses NK cell and T cell surveillance after therapy-induced senescence through enhancer of zeste homolog 2 (EZH2)-mediated epigenetic repression of proinflammatory SASP genes. EZH2 blockade stimulated production of SASP chemokines CCL2 and CXCL9/10, leading to enhanced NK cell 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 patients with PDAC. These results demonstrate that EZH2 represses the proinflammatory SASP and that EZH2 inhibition combined with senescence-inducing therapy could be a powerful means to achieve immune-mediated tumor control in PDAC.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > inflammation organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions diseases & disorders > cancer > cancer types > pancreatic cancer organism description > animal > mammal > rodent organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence diseases & disorders > cancer > cancer types
CSHL Authors:	Lowe, Scott W.
Communities:	CSHL labs > Lowe lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	June 2023
Date Deposited:	12 Oct 2023 19:30
Last Modified:	08 Jan 2024 18:25
PMCID:	PMC10516132
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41211

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