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

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. Overall design: RNA-seq analysis was performed on FACS sorted GFP+ KPC1 PDAC tumor cells harboring Renilla (Ren) or Ezh2 shRNA from KPC1 orthotopic PDAC tumors transplanted in the pancreas of C57BL/6 female mice following 2 week treatment with vehicle (V) or combined trametinib (1 mg/kg body weight) and palbociclib (100 mg/kg) (T/P).