Arginase 1-based immune modulatory vaccines induce anti-cancer immunity and synergize with anti-PD-1 checkpoint blockade
Menée à l'aide de modèles murins, cette étude met en évidence l'intérêt de vaccins utilisant des peptides dérivés de l'arginase ARG1 pour induire l'immunité antitumorale et démontre les effets synergiques de ces vaccins et des anti-PD1 sur l'infiltration de la tumeur par les lymphocytes T, l'expression de l'arginase ARG1, la fonction suppressive des cellules myéloïdes induites par les tumeurs et le rapport macrophages M1/macrophages M2 dans la tumeur
Expression of the L-arginine catabolizing enzyme arginase 1 (ARG1) is a central immunosuppressive mechanism mediated by tumor-educated myeloid cells. Increased activity of ARG1 promotes the formation of an immunosuppressive microenvironment and leads to a more aggressive phenotype in many cancers. Intrinsic T-cell immunity against ARG1-derived epitopes in the peripheral blood of cancer patients and healthy subjects has previously been demonstrated. To evaluate the anti-tumor efficacy of ARG1-derived peptide vaccines as a monotherapy and combinational therapy with checkpoint blockade, different in vivo syngeneic mouse tumor models were utilized. To evaluate the anti-tumor effects, flow cytometry analysis and immunohistochemistry were performed on tumors, and ELISPOT assays were performed to characterize immune responses. We show that ARG1-targeting therapeutic vaccines were able to activate endogenous anti-tumor immunity in several in vivo syngeneic mouse tumor models and to modulate the cell composition of the tumor microenvironment, without causing any associated side effects or systemic toxicity. ARG1-targeting vaccines in combination with anti-PD-1 also resulted in increased T-cell infiltration, decreased ARG1 expression, reduced suppressive function of tumor-educated myeloid cells, and a shift in the M1/M2 ratio of tumor-infiltrating macrophages. These results indicated that the induced shift towards a more pro-inflammatory microenvironment by ARG1-targeting immunotherapy favors effective tumor control when combined with anti-PD-1 checkpoint blockade. Our data illustrate the ability of ARG1-based immune modulatory vaccination to elicit antigen-specific immunosurveillance and imply the feasibility of this novel immunotherapeutic approach for clinical translation.