EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance Journal Article
| Authors: | Chibaya, L.; Murphy, K. C.; DeMarco, K. D.; Gopalan, S.; Liu, H.; Parikh, C. N.; Lopez-Diaz, Y.; Faulkner, M.; Li, J.; Morris, J. P. 4th; Ho, Y. J.; Chana, S. K.; Simon, J.; Luan, W.; Kulick, A.; de Stanchina, E.; Simin, K.; Zhu, L. J.; Fazzio, T. G.; Lowe, S. W.; Ruscetti, M. |
| Article Title: | EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance |
| 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. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc. |
| Keywords: | survival; cancer survival; controlled study; gene mutation; human cell; genetics; histopathology; nonhuman; cancer patient; pancreatic neoplasms; flow cytometry; cd8+ t lymphocyte; t lymphocyte; tumor associated leukocyte; mouse; phenotype; animal; animals; mice; animal tissue; gene; gene expression; cell infiltration; tumor volume; carcinoma, pancreatic ductal; green fluorescent protein; animal experiment; animal model; cytotoxicity; immunofluorescence; tumor xenograft; cell line, tumor; computer language; protein p53; cancer therapy; dna methylation; carcinogenesis; pancreas carcinoma; cancer inhibition; granzyme b; cellular immunity; chemokine; immunogenicity; pancreas tumor; cd4+ t lymphocyte; tumor cell line; western blotting; lentivirus vector; cell migration; natural killer cell; tumor immunity; real time polymerase chain reaction; microenvironment; senescence; myofibroblast; tumor growth; cancer control; gamma interferon inducible protein 10; immunosuppressive treatment; immunosurveillance; tumor gene; clonogenic assay; fluorescence activated cell sorting; transcriptome; bioluminescence; monocyte chemotactic protein 1; rna sequence; stromelysin; kidney transplantation; cancer transplantation; cxcl9 chemokine; cytotoxic lymphocyte; mouse model; tumor microenvironment; genotyping; transcription factor ezh2; ezh2 protein, mouse; short tandem repeat; pancreatic ductal carcinoma; pancreatic carcinoma; spermidine; tumor immunogenicity; trametinib; tumor spheroid; enhancer of zeste homolog 2 protein; sanger sequencing; senescence-associated secretory phenotype; human; male; female; article; palbociclib; vanadate sodium; epigenetic repression; cell migration assay; chemokine signaling; transcription factor ezh2 gene |
| Journal Title: | Nature Cancer |
| Volume: | 4 |
| Issue: | 6 |
| ISSN: | 2662-1347 |
| Publisher: | Nature Research |
| Date Published: | 2023-06-01 |
| Start Page: | 872 |
| End Page: | 892 |
| Language: | English |
| DOI: | 10.1038/s43018-023-00553-8 |
| PUBMED: | 37142692 |
| PROVIDER: | scopus |
| PMCID: | PMC10516132 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding author is MSK author Scott Lowe -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work