PD-1 Blockade and OX40 Triggering Synergistically Protects against Tumor Growth in a Murine Model of Ovarian Cancer
et al. (2014) PD-1 Blockade and OX40 Triggering Synergistically Protects against Tumor Growth in a Murine
Model of Ovarian Cancer. PLoS ONE 9(2): e89350. doi:10.1371/journal.pone.0089350
PD-1 Blockade and OX40 Triggering Synergistically Protects against Tumor Growth in a Murine Model of Ovarian Cancer
Zhiqiang Guo 0
Xin Wang 0
Dali Cheng 0
Zhijun Xia 0
Meng Luan 0
Shulan Zhang 0
Hiroshi Shiku, Mie University Graduate School of Medicine, Japan
0 1 Department of Gynecology and Obstetrics, Shengjing Hospital, China Medical University , ShenYang , China , 2 Department of Gynecology and Obstetrics, No. 306 Hospital of PLA , Beijing , China , 3 Department of Gynecology and Obstetrics, The First Affiliated Hospital, China Medical University , Shen Yang , China
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-c 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.
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Funding: This work was supported by the Free Researcher Project of Shengjing Hospital (No.200806). The funders had no role in study design, data collection
and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
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. Early
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]. Although most patients are
responsive to chemotherapy at first, the majority of them will
eventually have a relapse and die of the disease. Therefore, novel
strategies are urgently needed to improve the outcomes of ovarian
cancer.
Accumulating evidence suggests that immunotherapy should be
effective for OC treatment [5]. Firstly, OC cells express many
tumor-associated antigens against which specific immune
responses have been detected [610]. Secondly, the studies pioneered by
Coukos and colleagues indicate tumor immune response is a
critical determinant of clinical outcomes of patients with OC
supported by the close correlation between survival of these
patients and tumor infiltration with CD3+ T cells in the large
annotated clinical samples [11]. Thirdly, although OC is a
devastating disease, metastases are frequently restricted to the
peritoneal cavity where the tumor microenvironment is directly
accessible, which obviates the need for systemic delivery of
immunostimulatory treatments [12]. Despite the abundant
evidence supporting OC immunotherapy, clinical success with
immune-based therapies for OC has generally been modest [13].
Programmed Death 1 (PD-1) protein is a key coinhibitory
receptor on T cells with a structure similar to that of CTLA-4 but
with a distinct biologic function and ligand specificity [14]. PD-1
functions primarily i (...truncated)