Guadecitabine, in combination with a TLR9 agonist, promotes anti-cancer immunity in BALB/c mice bearing 4T1 mouse mammary carcinoma

Abstract

Abstract The classical approach to vaccine development establishes an effective, lasting memory response by challenging an organism with an antigen/adjuvant combination to prime the immune system against the antigen challenge. However, with respect to cancer vaccine development, this approach has often failed to elicit positive outcomes. This is, in part, due to the ability of tumor cells to downregulate specific antigens and forego immune surveillance. The objective of this study is to develop a treatment strategy that induces expression of cancer testis antigens (CTAs) on tumor cells while eliciting a strong and lasting immune response against these CTAs. CTAs are derived from proteins only expressed in immune-privileged sites under normal conditions, but de novo expression can be induced following treatment with a DNA methyltransferase inhibitor, such as guadecitabine (GUA). Previous publications have shown that intratumoral injections of a TLR9 agonist, CpG, results in an immune response against antigens expressed within the treated tumor. Our experiments have shown that 4T1 cells, a mouse mammary carcinoma, treated in vitro with GUA resulted in increased expression of CTAs as measured by flow cytometry. In addition, BALB/c mice challenged with 4T1 cells then treated with GUA + CpG resulted in depletion of myeloid derived suppressor cells and significantly reduced tumor burden. Tumor-bearing mice that received GUA treatment followed by adoptive T-cell therapy (ATC) also had significantly smaller tumors compared to the ATC only group. These findings warrant further investigation into whether treatment with GUA prior to treatment with CpG results in a lasting memory response against CTAs.