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.

Arginase 1-based immune modulatory vaccines induce anti-cancer immunity and synergize with anti-PD-1 checkpoint blockade

Iezzi, Manuela;
2021

Abstract

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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11564/757525
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