Abstract
BackgroundEndoplasmic reticulum stress has a profound effect on cancer cell proliferation and survival, and also has the capacity to activate cells of the adaptive immune system. Multimodal treatment methods that utilize and combine conventional cancer therapies with antigen-specific immunotherapies have emerged as promising approaches for the treatment and control of cancer. However, it is not well known whether endoplasmic reticulum stress-inducing agents can influence the efficacy of tumor antigen-targeting vaccines.MethodsIn the past, we developed a therapeutic human papillomavirus (HPV) DNA vaccine that encodes for calreticulin (CRT) linked to the HPV16 E7 antigen (CRT/E7). In this study, we utilize the CRT/E7 and further encode for an endoplasmic reticulum (ER) stress-inducing agent, 3-bromopyruvate (3-BrPA), in a preclinical model, by harnessing its potential to enhance HPV16 E7-specific CD8+ T cell immune responses as well as antitumor effects against E7-expressing tumors (TC-1 cells). E7-specific CD8+ T cells were added to evaluate the cytotoxicity of luciferase-expressing TC-1 tumor cells treated with 3-BrPA in vitro, as measured with an IVIS Luminescence Imaging System. We also determined the levels of ER stress markers in 3-BrPA-treated TC-1 cells. TC-1 tumor-bearing mice were treated with either 3-BrPA (10 mg/kg, intraperitoneal injection) and/or CRT/E7 DNA vaccine (30 μg/mouse).ResultsTreatment of E7-expressing TC-1 tumor cells with 3-BrPA induced significantly higher in vitro cytotoxicity and resulted in upregulation of endoplasmic reticulum stress markers (CHOP and GRP78). More importantly, combination treatment of 3-BrPA and the CRT/E7 DNA vaccine led to improved antigen-specific CD8+ T cell immune responses as well as therapeutic antitumor effects in TC-1 tumor-bearing mice.ConclusionsOur data indicate that 3-BrPA can enhance therapeutic HPV vaccine potency in generating improved antigen-specific immune responses and antitumor effects. These findings have important implications for future clinical translation and provide novel strategies for the treatment of HPV-associated diseases.
Highlights
Endoplasmic reticulum stress has a profound effect on cancer cell proliferation and survival, and has the capacity to activate cells of the adaptive immune system
PD-1/ PD-L1 and CTLA-4 monoclonal antibodies have significantly improved the survival of metastatic melanoma patients, producing durable responses in about 20–40% of patients when used as monotherapies, and in up to 60% of the combination therapy [24, 32]
We found that while 3-BrPA elicited antitumor effects in TC-1 tumorbearing mice, the combination of 3-BrPA and CRT/pcDNA3-CRT/E7 vaccine (CRT/E7) vaccine (E7) created a synergistic effect leading to the generation of significantly more E7-specific CD8+ T cells in the spleen compared to treatment with either treatment alone
Summary
Endoplasmic reticulum stress has a profound effect on cancer cell proliferation and survival, and has the capacity to activate cells of the adaptive immune system. Multimodal treatment methods that utilize and combine conventional cancer therapies with antigen-specific immunotherapies have emerged as promising approaches for the treatment and control of cancer. It is not well known whether endoplasmic reticulum stress-inducing agents can influence the efficacy of tumor antigen-targeting vaccines. Treatments such as immune checkpoint inhibitors have shown a strong therapeutic effect in several cancer treatments, while other immunotherapies are gradually receiving more attention in cancer therapy [2, 13, 28]. Additional strategies are required in an attempt to enhance DNA vaccine potency
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