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Abstract
DNA vaccination against cancer has become a promising strategy for inducing a specific and long-lasting antitumor immunity. However, DNA vaccines fail to generate potent immune responses when used as a single therapy. To enhance their activity into the tumor, a DNA vaccine against murine P815 mastocytoma was combined with antibodies directed against the immune checkpoints CTLA4 and PD1. The combination of these two strategies delayed tumor growth and enhanced specific antitumor immune cell infiltration in comparison to the corresponding single therapies. The combination also promoted IFNg, IL12 and granzyme B production in the tumor microenvironment and decreased the formation of liver metastasis in a very early phase of tumor development, enabling 90% survival. These results underline the complementarity of DNA vaccination and immune checkpoint blockers in inducing a potent immune response, by exploiting the generation of antigen-specific T cells by the vaccine and the ability of immune checkpoint blockers to enhance T cell activity and infiltration in the tumor. These findings suggest how and why a rational combination therapy can overcome the limits of DNA vaccination but could also allow responses to immune checkpoint blockers in a larger proportion of subjects.
Highlights
Immunotherapy is an established approach to treat cancer based on the observation that the immune system can mount destructive responses against tumors
This encouraging result suggests the possibility to reduce the dose of immune checkpoint blockers (ICBs) when they are administered in combination with DNA vaccination, to decrease the toxicities associated to these antibodies in human patients[12]
This study evaluates the main limitations of the use of DNA vaccines and ICB as single treatment against cancer
Summary
Immunotherapy is an established approach to treat cancer based on the observation that the immune system can mount destructive responses against tumors. Activated T cells express inhibitory receptors on their surface, such as CTLA4 and PD1, aiming at preventing autoimmunity[3] These receptors are responsible for the lack of effective antitumor immune responses in cancer patients, dampening T cell effector activity against tumor antigens. PD-1 transmits inhibitory signals into T cells after ligation with PD-1 ligands and promotes tolerance[5] Antibodies blocking these molecules can increase the effector activity of tumor-specific T cells[6]. With anti-CTLA4 is approximately 12%3, indicating the need for improvement This low efficacy may be due to a lack of pre-existing tumor-associated T cell immunity. We demonstrated that the optimized vaccine increased antigen expression and activated innate immunity while retarding tumor growth in both preventive and therapeutic settings[10]. We evaluated the effects of the two strategies in the tumor microenvironment (TME) in an early phase of tumor development and metastasis formation that, until now, has been poorly explored
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