Atezolizumab and Bevacizumab Attenuate Cisplatin Resistant Ovarian Cancer Cells Progression Synergistically via Suppressing Epithelial-Mesenchymal Transition

Abstract

The AURELIA trial demonstrated that adding Bevacizumab to chemotherapy significantly improved progression-free survival (PFS) for platinum resistant recurrent ovarian cancer. Recently, immunotherapy also presented potential anti-tumor effects in several malignant solid tumors. This study aimed to investigate whether combining anti-PD-L1 Atezolizumab with BEV may have a synergistic effect and enhance the efficacy of both treatments in cisplatin resistant epithelial ovarian cancer (CREOC). We retrospectively analyzed 124 epithelial ovarian cancer (EOC) patients from Gynecologic Oncology Department of Tianjin Cancer Hospital between January 2013 and June 2018, who all were diagnosed with cisplatin resistance due to progressing <6 months after completing platinum-based therapy. Based on responding to at least 2 cycles of Bevacizumab-containing chemotherapy (BC), these Patients were divided into BC response group and BC non-response group. Immunohistochemistry was used to detect that PD-L1 expression and tumor angiogenesis-related proteins (VEGF and Semaphorin4D) in tissues from 124 patients with CREOC. The positive expressions of PD-L1, VEGF, and Semaphorin4D (SEMA4D) were found in 58.73, 50.79, and 71.43% of the 63 cases CREOC tissues with BC response, respectively, which were significantly higher than that in the 61 cases BC non-response group ( P < 0.05). PD-L1 expression correlated with SEMA4D and VEGF positively ( r = 0.344 and 0.363, P < 0.001). Over-expressions of PD-L1, VEGF and SEMA4D are associated with more malignant clinicopathologic characteristics of CREOC Patients. In survival analysis, patients' response to BC was the independent factor for evaluation of PFS and overall survival (OS). Cell functional assays showed that Atezolizumab in combination with Bevacizumab inhibited the proliferation, migration, and invasion of cisplatin resistant ovarian cancer cell line A2780cis in vitro synergistically, which maybe associate with Bevacizumab suppressing the epithelial-mesenchymal transition (EMT) and PD-L1 expression by targeting STAT3. Furthermore, Bevacizumab and Atezolizumab induced synergistic anti-tumor effect in vivo . These findings suggest a novel therapeutic strategy for cisplatin resistant recurrent EOC and its mechanism warrants further study.

The Role of Epithelial-to-Mesenchymal Plasticity in Ovarian Cancer Progression and Therapy Resistance

“…Notably, anti-VEGF treatment suppressed PD-L1 expression and EMT via decreased STAT3 phosphorylation in cisplatin resistant ovarian cancer cells. Moreover, anti-VEGF and anti-PD-L1 agents acted synergistically to reduce tumor growth in vivo, which might have been due to enhancement of the immunotherapy efficacy by the anti-EMT effect of the anti-VEGF treatment [166].…”

The Perfect Combination: Enhancing Patient Response to PD-1-Based Therapies in Epithelial Ovarian Cancer

“…In addition, the authors discovered that atezolizumab and bevacizumab in combination substantially inhibited cisplatin-resistant ovarian cancer cell proliferation, migration and invasion, which they attributed to the impediment of EMT through the signal transducer and activator of transcription 3 (STAT3) pathway. Finally, an in vivo mouse model demonstrated synergistic reduction in tumor burden in the mice treated with atezolizumab and bevacizumab compared to either monotherapy alone [ 21 ]. While these results appear promising and suggest non-immune mediated effects of PD-1-based treatments, as this study was not performed in an immunocompetent model, a deficiency remains in our understanding of how these therapies act in concert to promote anti-tumor immunity.…”

“…These results indicate that PD-1 therapy alone will not be efficacious enough to improve survival for EOC patients. However, evidence is emerging that combinatorial methods will be critical to optimizing EOC patient response to immunotherapy [ 21 ].…”

VEGF-A Is Associated With the Degree of TILs and PD-L1 Expression in Primary Breast Cancer

“…Vascular endothelial growth factor-A (VEGF-A), one of the most important angiogenic factors (1-3), has been reported to effect cancer growth and development (3)(4)(5)(6). VEGF-A is also involved in the regulation of immune response in various cancers (3,(7)(8)(9)(10)(11)(12)(13)(14). Recent reports have indicated that anti-VEGF therapy has the important effect of enhancing anti-tumor immunity in various cancers (3,(7)(8)(9)(10)(11)(12)(13)(14).…”

“…VEGF-A is also involved in the regulation of immune response in various cancers (3,(7)(8)(9)(10)(11)(12)(13)(14). Recent reports have indicated that anti-VEGF therapy has the important effect of enhancing anti-tumor immunity in various cancers (3,(7)(8)(9)(10)(11)(12)(13)(14). The immune system affects tumor progression and dissemination, and treatment response (15)(16)(17)(18).…”