Abstract
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.
Highlights
Ovarian carcinoma (OC) is the most lethal malignancy in women, with 22,280 new cases and 15,460 deaths estimated in the United States for 2012 [1]
We did not detect any expression of Programmed Death-1 (PD-1) and OX40 molecules and their respective ligands PD-L1/PD-L2 and OX40L on the surface of ID8 ovarian cancer cells, excluding the possibility that inhibition of ID8 tumor growth in vivo is directly mediated by anti-PD-1 or anti-OX40 Monoclonal Antibodies (mAbs)
Combined anti-PD-1/OX40 mAb treatment fostered a local immunostimulatory microenvironment To further substantiate the shifting of tumor microenvironment, we examined the expression of immune-associated genes in freshly isolated peritoneal immune cells (PIC) on days 3 to 7 after mAb treatment
Summary
Ovarian carcinoma (OC) is the most lethal malignancy in women, with 22,280 new cases and 15,460 deaths estimated in the United States for 2012 [1]. The high rate of lethality from OC is primarily due to the advanced stage of disease at diagnosis. Stage cancers can be cured in up to 90% of patients with current therapies [2], but this rate drops substantially for advanced disease with approximately 30% of patients with advanced stage OC survive 5 years after initial diagnosis [3]. The standard treatment for ovarian cancer is surgical debulking followed by platinumtaxane based chemotherapy [4]. Most patients are responsive to chemotherapy at first, the majority of them will eventually have a relapse and die of the disease. Novel strategies are urgently needed to improve the outcomes of ovarian cancer
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