Epigenetic modulation enhances immunotherapy for pancreatic ductal adenocarcinoma

Abstract

Objectives Pancreatic ductal adenocarcinoma ( PDAC ) is an aggressive disease with a poor prognosis. PDAC has poor response to immunotherapy because of its unique tumour microenvironment ( TME ). In an attempt to stimulate immunologically silent pancreatic cancer, we investigated the role of epigenetic therapy in modulating the TME to improve immunogenicity. Methods In vitro human PDAC cell lines MiaPaca2 and S2 ‐013 were treated with 5 μ m 3‐Deazaneplanocin A ( DZNep , an EZH2 inhibitor) and 5 μ m 5‐Azacytidine ( 5‐AZA , a DNMT1 inhibitor). In vivo orthotopic murine tumour models using both murine PAN02 cells and KPC cells inoculated in immunocompetent C56 / BL7 mice were treated with anti‐PD‐L1 combined with DZNep and 5‐AZA . Short hairpin knockdown ( KD ) of EZH2 and DNMT1 in PAN02 cells for the orthotopic murine tumour model was established to validate the drug treatment ( DZNep and 5‐AZA ). qRT‐PCR and microarray assays were performed for the evaluation of Th1‐attracting chemokines and cancer‐associated antigen induction. Results Drug treatments induced significant upregulation of gene expressions of Th1‐attracting chemokines, CXCL9 and CXCL10 , and the cancer–testis antigens, NY‐ESO‐1 , LAGE and SSX‐4 ( P < 0.05). In orthotopic tumour models, inoculation of PAN02 cells or KPC cells demonstrated significant tumour regression with corresponding increased apoptosis and infiltration of cytotoxic T lymphocytes in the combination treatment group. In the orthotopic Pan02‐KD model, the anti‐PD‐L1 treatment also caused significant tumour regression. Conclusion We demonstrate that immunotherapy for PDAC can be potentiated with epigenetic therapy by increasing cancer‐associated antigen expression and increased T‐cell trafficking across the immunosuppressive tumour microenvironment via upre...

PD-L1 Downregulation and DNA Methylation Inhibition for Molecular Therapy against Cancer Stem Cells in Hepatocellular Carcinoma

“…In pancreatic ductal adenocarcinoma, it was shown that immunotherapy using anti-PD-L1 can be potentiated with epigenetic therapy (DZNep and 5-AZA) by increasing cancer-associated antigen expression and increasing T cell trafficking across the immunosuppressive tumor microenvironment [30]. It is also in line with a previous study in HCC cells (HepG2, Hep3B, and Hepa1-6) treated with 5-AZA (and DZNep) with and without anti-PD-L1.…”

Targeting one‐carbon metabolism for cancer immunotherapy

“…50,51 Treatment with DNMT1 inhibitors, such as DZNep, could enhance effector T-cell tumour infiltration and increase the response of patients to PD-1/PD-L1 inhibitors and adoptive T-cell transfusion. 47,[71][72][73][74][75] In conclusion, DNMT1 might be a promising target for cancer immunotherapy.…”

“…Suppression of DNMT1 could result in the upregulation of the immune checkpoint proteins human leukocyte antigen G and indoleamine 2,3‐dioxygenase, which provided targets for cancer immunotherapy 50,51 . Treatment with DNMT1 inhibitors, such as DZNep, could enhance effector T‐cell tumour infiltration and increase the response of patients to PD‐1/PD‐L1 inhibitors and adoptive T‐cell transfusion 47,71–75 . In conclusion, DNMT1 might be a promising target for cancer immunotherapy.…”

Novel insights into TCR-T cell therapy in solid neoplasms: optimizing adoptive immunotherapy

“…Primary resistance arises from tumor antigenic characteristics, including antigenic expression drift, heterogeneity, or low antigenic expression [ 308 ], especially in cancers carrying high mutational loads. The genetic heterogeneity in the targeting of TCRs to some limited neoantigen also leads to functional limitations of TCR-T cells that accompany this heterogeneity, analogous to the inactivation of ICIs [ 309 ], and the tumor epigenetic heterogeneity of patients also generates antigenic variants and generates new TCR tolerance [ 310 – 312 ]. Thus, the need for shared antigenicity has been emphasized during TCR development, in order to provide deep coverage of tumor tissues in both spatial and temporal dimensions, better selection of early key antigens with less susceptibility to antigenic drift is needed, as well as an emphasis on achieving broadness in the individualization of the antigenic screening process, in a single dose or in phases, by administering therapies targeting multiple target antigens.…”