TY - JOUR

T1 - Arginase 1–Based immune modulatory vaccines induce anticancer immunity and synergize with Anti–PD-1 checkpoint blockade

AU - Jørgensen, Mia Aaboe

AU - Ugel, Stefano

AU - Hübbe, Mie Linder

AU - Carretta, Marco

AU - Perez-Penco, Maria

AU - Weis-Banke, Stine Emilie

AU - Martinenaite, Evelina

AU - Kopp, Katharina

AU - Chapellier, Marion

AU - Adamo, Annalisa

AU - de Sanctis, Francesco

AU - Frusteri, Cristina

AU - Iezzi, Manuela

AU - Zocca, Mai Britt

AU - Madsen, Daniel Hargbøll

AU - Pedersen, Ayako Wakatsuki

AU - Bronte, Vincenzo

AU - Andersen, Mads Hald

N1 - Publisher Copyright: © 2021 American Association for Cancer Research.

PY - 2021

Y1 - 2021

N2 - 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 antitumor efficacy of ARG1-derived peptide vaccines as a monotherapy and as a combinational therapy with checkpoint blockade, different in vivo syngeneic mouse tumor models were utilized. To evaluate the antitumor effects, flow cytometry analysis and IHC 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 antitumor 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 toward a more proinflammatory 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.

AB - 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 antitumor efficacy of ARG1-derived peptide vaccines as a monotherapy and as a combinational therapy with checkpoint blockade, different in vivo syngeneic mouse tumor models were utilized. To evaluate the antitumor effects, flow cytometry analysis and IHC 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 antitumor 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 toward a more proinflammatory 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.

U2 - 10.1158/2326-6066.CIR-21-0280

DO - 10.1158/2326-6066.CIR-21-0280

M3 - Journal article

C2 - 34518197

AN - SCOPUS:85119129013

VL - 9

SP - 1316

EP - 1326

JO - Cancer Immunology Research

JF - Cancer Immunology Research

SN - 2326-6066

IS - 11

ER -