Abstract
Immune checkpoint blockade therapy has been the most recent advance for achieving durable clinical response of different advanced cancers. However, most patients still remain non-responsive to immunotherapy alone, which suggest the need for combining different cancer therapies. Dual blockade targeting CTLA-4 and PD1/PDL1 pathway have been explored in advance melanoma, renal cell cancer, and NSCLC with promising clinical evidence. Though it is still unclear which sequence of checkpoint blockade therapies is the most effective. Another combinatorial strategy for cancer treatment would be combing epigenetic therapy with immunotherapy. Low doses of the DNA methylation inhibitor (DNMTis), 5-AZA-CdR, on cancer cells has durable anti-tumorigenic effects by inducing cell cycle arrest and immune-modulatory effects that increases their visibility by the immune system. Growing evidence led by our group and others suggest that DNMTis can upregulate immune signalling in cancer cells through viral mimicry and upregulation of tumor associated antigens, highlighting clinical potential to combine with immunotherapy. While the effects of DNMTis have been mostly studied in cancer cells, their effects on the immune system remains vastly unknown specially at clinically relevant low doses. The goal was to study the effects of 5-AZA-CdR on CD8+ T cells due to their inherent cytotoxic functions to recognize and kill pathogen infected cells and tumor cells. Because DNA methylation is a known mechanism by which CD8+ T cells can regulate the transcription of genes encoding for effector cytokines such as IFN-gamma, we hypothesize that treatment of 5-AZA-CdR during CD8+ T cell expansion will allow more permissive transcription of effector cytokines genes, thus conferring enhanced CD8+ T cell effector function. We used human CD8+ T cells expanded with anti-CD3/CD28 beads in the presence or absence of lose dose 5-AZA-CdR. Our results indicate that while low dose 5-AZA-CdR treatment during human CD8+ T cell expansion reduced CD8+ T cell proliferation capacity and increased expression of various T cell inhibitory receptors, functional capacity of CD8+ was improved. Low dose 5-AZA-CdR treatment during human CD8+ T cell expansion conferred higher expression and production of the effector cytokines IFN-gamma and TNF-alpha, and the cytotoxic granules Granzyme B. These observations suggest that treatment with 5-AZA-CdR during CD8+ T cells expansion may enhance their cytotoxic functions. By studying the effects of 5-AZA-CdR on CD8+ T cells, our goal is to use this knowledge generated in here to help elucidate rational combinatorial regimens for epigenetic therapy and immunotherapy.
Citation Format: Helen Loo Yau. Characterizing the effects of the DNA methylation inhibitor 5-AZA-CdR during CD8 T cell expansion [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B053.
