化学療法抵抗性卵巣癌の局所免疫の解析に基づいた,がん免疫逃避を標的とした新規治療戦略(シンポジウム2(腫瘍) 難治性卵巣癌の克服を目指して,第66回日本産科婦人科学会学術講演会講演要旨)

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  • 濱西,潤三
    京都大学大学院医学研究科器官外科学講座婦人科学産科学

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  • Development of a Novel Therapeutic Strategy Targeting Cancer Immune Escape Based on Local Immunological analysis of Chemo-resistant Ovarian Cancer

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Background: Ovarian cancer is the most lethal gynecologic malignancy in the world and the fourth most common cause of cancer death in women, largely because more than 75% of patients are diagnosed at advanced tumor status (stage III or IV). Although taxane and platinum-based chemotherapies are effective in the treatment of the majority of ovarian cancer cases, over 70% of patients suffer from recurrence and eventually develop chemo-resistance. Considering the high mortality rate of ovarian cancer, which is due to the absence of curative treatment at advanced stages or at recurrence, new therapeutic modalities to complement chemotherapy, including immunotherapy, are urgently needed. Tumor immune therapy has long been considered as an alternative modality for the treatment of solid tumors, including ovarian cancer. However, few reports have described clinically successful immune therapies. The failure of immune therapies in such clinical trials can be partly ascribed to the phenomenon designated as "cancer immune escape", which involves PD-1/PD-L1 signaling. It is becoming clear that the dynamic interaction between tumor cells and immune cells in the local microenvironment plays a pivotal role in cancer development and progression. However, few studies have addressed both the immune-suppressive mechanism of the ovarian tumor microenvironment and the alteration of local immune status by chemotherapy. Therefore, in this study, we examined the cancer immune escape system in advanced ovarian cancer and the molecular mechanism of chemotherapy-induced PD-L1 expression in human ovarian cancer cells. In addition, using a syngenic mouse ovarian cancer model, we investigated whether inhibition of the PD-1/PD-L1 signal can induce an anti-tumor effect in a clinical setting and increase the efficacy of chemotherapy. Method: First, we attempted to explore the status of local immunity in ovarian cancers by integrating various immunological p arameters, determined by immunohistochemical analysis of clinical specimens, and validated these results in a mouse ovarian cancer model. Second, we focused on immunological phenomena, including PD-L1 expression in tumor cells in peritoneal dissemination of ovarian cancer. We used flow cytometry to monitor PD-L1 expression in mouse ovarian cancer cell lines under various conditions. Next, we generated PD-L1-overexpressing and PD-L1-depleted cell lines, and analyzed cytolysis by T cells following co-culture with these cells. In addition, we intraperitoneally injected these cell lines into syngeneic mice and analyzed the survival times of these animals. Third, we analyzed microarray-based gene-expression datasets from clinical ovarian cancer samples collected before and after chemotherapy. In addition, we examined the relationship between PD-L1 overexpression and NF-kB signaling activation following treatment with chemotherapeutic agents, and evaluated chemotherapy-induced local tumor immune suppression by PD-L1 overexpression in ovarian cancer. Next, we investigated whether the blockade of PD-L1 intumor cells reversed the decline in T-cell immunity and promoted tumor rejection after chemotherapy in a mouse ovarian cancer model. Fourth, on the basis of the aforementioned experiments, we initiated a proof-of-concept clinical trial of anti-PD-1 antibody (Nivolumab) in patients with ovarian cancer at Kyoto University Hospital. Results: First, among 11 immune-related factors monitored by immunohistochemistry in ovarian cancer samples, tumor-infiltrating CD8+ T-cell count was a favorable prognostic factor, whereas expression of PD-L1 on tumor cells was predictive of poor prognosis. In addition, the survival times of mice with ovarian cancer were prolonged when we could induce infiltration of immune cells, including CD8+ T cells, into tumor sites. Second, microarray analysis and immunohistochemistry in human ovarian cancers revealed a significant correlation between PD-L1 e xpression and peritoneal dissemination. PD-L1 expression in mouse ovarian cancer cells was induced when tumor cells encountered T cells during peritoneal spread in vivo or co-culture with T cells in vitro. Tumor cell lysis by CTLs was attenuated when PD-L1 was overexpressed, and promoted when it was silenced.PD-L1 overexpression inhibited gathering and degranulation of CTLs. In mouse models, PD-L1 depletion inhibited tumor growth in the peritoneal cavity and prolonged survival. Third, several chemotherapeutic agents induced PD-L1 expression through NF-κB signaling in ovarian cancer, resulting in local immune suppression. These results suggest that immunotherapy targeting the PDL1/PD-1 signaling pathway, in combination with chemotherapy, represents a promising new treatment modality against ovarian cancer that could achieve a more effective antitumor response. Fourth, in 2011, we started a physician-initiated medical phase II clinical trial, "Efficacy and safety of anti-PD-1 antibody (Nivolumab: BMS-936558, ONO-4538) in patients with platinum-resistant ovarian cancer." This trial was completed in March 2014, because all twenty patients were enrolled in March 2014. Summary: The results of this study suggested that immunosuppressive factors might influence the pattern of tumor infiltration by immune cells. The analyses described here may lead to a precise understanding of the local immune status and provide a tool for the application of therapeutic anti-PD-1 antibody to treatment of ovarian cancer patients. In addition, we found that chemotherapeutic agents upregulate PD-L1 expression through activation of NF-kB signaling. Thus, immunotherapeutic targeting of PDL1/PD-1 signaling, in combination with chemotherapy, represents a promising treatment modality against ovarian cancer.

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