Journal Article

PD-1 Blockade and OX40 Triggering Synergistically Protects against Tumor Growth in a Murine Model of Ovarian Cancer

Zhang, Shulan, Xia, Zhijun, Guo, Zhiqiang, Cheng, Dali, Luan, Meng, Wang, Xin

2014

Overview

The co-inhibitory receptor Programmed Death-1 (PD-1) curtails immune responses and prevent autoimmunity, however, tumors exploit this pathway to escape from immune destruction. The co-stimulatory receptor OX40 is upregulated on T cells following activation and increases their clonal expansion, survival and cytokine production when engaged. Although antagonistic anti-PD-1 or agonistic anti-OX40 antibodies can promote the rejection of several murine tumors, some poorly immunogenic tumors were refractory to this treatment. In the present study, we evaluated the antitumor effects and mechanisms of combinatorial PD-1 blockade and OX40 triggering in a murine ID8 ovarian cancer model. Although individual anti-PD-1 or OX40 mAb treatment was ineffective in tumor protection against 10-day established ID8 tumor, combined anti-PD-1/OX40 mAb treatment markedly inhibited tumor outgrowth with 60% of mice tumor free 90 days after tumor inoculation. Tumor protection was associated with a systemic immune response with memory and antigen specificity and required CD4(+) cells and CD8(+) T cells. The anti-PD-1/OX40 mAb treatment increased CD4(+) and CD8(+) cells and decreased immunosuppressive CD4(+)FoxP3(+) regulatory T (Treg) cells and CD11b(+)Gr-1(+) myeloid suppressor cells (MDSC), giving rise to significantly higher ratios of both effector CD4(+) and CD8(+) cells to Treg and MDSC in peritoneal cavity; Quantitative RT-PCR data further demonstrated the induction of a local immunostimulatory milieu by anti-PD-1/OX40 mAb treatment. The splenic CD8(+) T cells from combined mAb treated mice produced high levels of IFN-γ upon tumor antigen stimulation and exhibited antigen-specific cytolytic activity. To our knowledge, this is the first study testing the antitumor effects of combined anti-PD-1/OX40 mAb in a murine ovarian cancer model, and our results provide a rationale for clinical trials evaluating ovarian cancer immunotherapy using this combination of mAb.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Animal models / Animals / Antibodies / Antibodies, Monoclonal - administration & dosage / Antibodies, Monoclonal - pharmacology / Anticancer properties / Antigens / Antigens, Neoplasm - immunology / Antineoplastic Agents - administration & dosage / Antineoplastic Agents - pharmacology / Antitumor activity / Apoptosis / Autoimmunity / Biology / Cancer / Cancer immunotherapy / Cancer therapies / CD11b antigen / CD4 antigen / CD8 antigen / Cell activation / Cell Line, Tumor / Cell survival / Chemotherapy / Clinical trials / Combinatorial analysis / Cytokines / Cytolytic activity / Cytotoxicity, Immunologic - drug effects / Disease Models, Animal / Effector cells / Epitopes, T-Lymphocyte / Female / Foxp3 protein / Gynecology / Hospitals / Immune response / Immune system / Immunogenicity / Immunoglobulins / Immunologic factors / Immunological memory / Immunostimulation / Immunosuppression / Immunotherapy / Inoculation / Interferon / Ligands / Lymphocytes / Lymphocytes T / Medical research / Medicine / Mice / Monoclonal antibodies / Myeloid Cells - drug effects / Myeloid Cells - immunology / Obstetrics / Ovarian cancer / Ovarian carcinoma / Ovarian Neoplasms - drug therapy / Ovarian Neoplasms - immunology / Ovarian Neoplasms - metabolism / Ovarian Neoplasms - mortality / Ovarian Neoplasms - pathology / PD-1 protein / Peritoneum / Polymerase chain reaction / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Programmed Cell Death 1 Receptor - metabolism / Receptors, OX40 - agonists / Receptors, OX40 - metabolism / Spleen / T cells / T-Lymphocyte Subsets - drug effects / T-Lymphocyte Subsets - immunology / T-Lymphocyte Subsets - metabolism / T-Lymphocytes, Cytotoxic - drug effects / T-Lymphocytes, Cytotoxic - immunology / Tumor Burden / Tumor Microenvironment - drug effects / Tumor Microenvironment - immunology / Tumors / γ-Interferon