DNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer

Abstract

Potentiating anti-tumor immunity by inducing tumor inflammation and T cell-mediated responses are a promising area of cancer therapy. Immunomodulatory agents that promote these effects function via a wide variety of mechanisms, including upregulation of antigen presentation pathways. Here, we show that major histocompatibility class-I (MHC-I) genes are methylated in human breast cancers, suppressing their expression. Treatment of breast cancer cell lines with a next-generation hypomethylating agent, guadecitabine, upregulates MHC-I expression in response to interferon-γ. In murine tumor models of breast cancer, guadecitabine upregulates MHC-I in tumor cells promoting recruitment of CD8+ T cells to the microenvironment. Finally, we show that MHC-I genes are upregulated in breast cancer patients treated with hypomethylating agents. Thus, the immunomodulatory effects of hypomethylating agents likely involve upregulation of class-I antigen presentation to potentiate CD8+ T cell responses. These strategies may be useful to potentiate anti-tumor immunity and responses to checkpoint inhibition in immune-refractory breast cancers.

5-Azacytidine Potentiates Anti-tumor Immunity in a Model of Pancreatic Ductal Adenocarcinoma

“…Hypomethylating agents, such as Aza, have the potential to meet this need. In gene expression data from breast cancer patients with matched biopsies before and after treatment with Aza and entinostat, the treatment increased the expression of multiple HLA molecules in all five patients (25). If a DNMTi such as Aza were able to increase MHC class I presentation of tumor antigens or IFN-γ responses in human PDAC, it may promote more favorable responses to current immunotherapies that PDAC, in general, has been highly refractive to Pu et al (60).…”

“…However, the observation that highly immunogenic TEs and TAAs significantly increase during transformation to PDAC, but do not cause a significant anti-tumor response to prevent progression and growth, would suggest that components involved in anti-viral immunity and/or antigen-presentation are compromised during this transition. In fact, recent studies in immunocompetent melanoma, ovarian, colorectal and breast cancer models (14,15,25) have shown that activation (i.e., upregulated expression) of TEs in conjunction with increased, innate type I interferon signaling and MHC class I expression, through DNMTi treatment, sensitizes tumor cells to immune attack, which contributes to dramatically decreased tumor growth. These data would suggest that the benefit of anti-TAA or -TE immunity to control tumor growth outweighs their tumor promoting activity.…”

“…Recent key studies have revealed that lowerdose treatments with DNMTi induce an anti-tumor immune response through increased expression of dsDNA intermediates of transposable elements or immune response genes (14,15). Interestingly, increased MHC I expression after DNMTi treatment, along with increased expression of anti-viral response genes, has been observed coincident with the regression of breast cancer and melanomas (25). Thus, DNMTi treatment as an anticancer therapy should be further studied for their potential to stimulate anti-tumor immune responses.…”

Hypomethylating agent alters the immune microenvironment in acute myeloid leukaemia (AML) and enhances the immunogenicity of a dendritic cell/AML vaccine

“…While the mechanism of action of HMAs in AML is diverse, there is increasing appreciation of immunomodulatory effects in mediating response. In solid tumour models, HMAs exert regulatory effects on the antigen presenting properties of malignant cells (Karpf, 2006;Woloszynska-Read et al, 2008;Akers et al, 2010;Almstedt et al, 2010;Goodyear et al, 2010;Srivastava et al, 2014;Ørskov et al, 2015). Pre-treatment of tumour cells with HMAs primes tumours to induce potent immune responses.…”

Toll‐like receptor 7/8‐matured RNA‐transduced dendritic cells as post‐remission therapy in acute myeloid leukaemia: results of a phase I trial

“…Epigenetic modifiers such as DNA methyltransferase inhibitors and histone deacetylase inhibitors are suitable combination partners because of an enhancement in antigen processing and presentation of malignant cells. [22][23][24][25] In the setting of myelodysplastic syndrome, the combination of vaccination against NY-ESO-1 and decitabine resulted in an increased antigen-specific immune response. 26 In our hands, the combination of next-generation DC vaccination with 5azacytidine resulted in a striking increase in local and systemic immune responses.…”