Genomics to immunotherapy of ovarian clear cell carcinoma: Unique opportunities for management

Abstract

Ovarian clear cell carcinoma (OCCC) is distinctive from other histological types of epithelial ovarian cancer, with genetic/epigenetic alterations, a specific immune-related molecular profile, and epidemiologic associations with ethnicity and endometriosis. These findings allow for the exploration of unique and specific treatments for OCCC. Two major mutated genes in OCCC are PIK3CA and ARID1A, which are frequently coexistent with each other. Other genes' alterations also contribute to activation of the PI3K (e.g. PIK3R1 and PTEN) and dysregulation of the chromatin remodeling complex (e.g. ARID1B, and SMARKA4). Although the number of focal copy number variations is small in OCCC, amplification is recurrently detected at chromosome 20q13.2 (including ZNF217), 8q, and 17q. Both expression and methylation profiling highlight the significance of adjustments to oxidative stress and inflammation. In particular, up-regulation of HNF-1β resulting from hypomethylation contributes to the switch from anaerobic to aerobic glucose metabolism. Additionally, up-regulation of HNF-1β activates STAT3 and NF-κB signaling, and leads to immune suppression via production of IL-6 and IL-8. Immune suppression may also be induced by the increased expression of PD-1, Tim-3 and LAG3. Mismatch repair deficient (microsatellite instable) tumors as found in Lynch syndrome also induce immune suppression in some OCCC. In a recent phase II clinical trial in heavily-treated platinum-resistant ovarian cancer, two out of twenty cases with a complete response to the anti-PD-1 antibody, nivolumab, were OCCC subtypes. Thus, the immune-suppressive state resulting from both genetic alterations and the unique tumor microenvironment may be associated with sensitivity to immune checkpoint inhibitors in OCCC. In this review, we highlight recent update and progress in OCCC from both the genomic and immunologic points of view, addressing the future candidate therapeutic options.

Pembrolizumab monotherapy in Japanese patients with advanced ovarian cancer: Subgroup analysis from the KEYNOTE‐100

“…Clear‐cell carcinoma is distinct from other histological types of EOC, with frequent genetic/epigenetic alterations of genes such as PIK3CA and ARID1A . Indeed, CCC has a specific immune‐related molecular profile and epidemiologic associations with ethnicity and endometriosis . Intriguingly, CCC is a major histologic subtype of renal cell carcinoma, with remarkable multifaceted mutational similarities between endometrial and renal CCC .…”

CD19-targeting fusion protein combined with PD1 antibody enhances anti-tumor immunity in mouse models

“…Meanwhile, scFv-D4 treatment also enhanced the infiltration of CD4 + Foxp3 + Treg cells in tumor tissues ( Figure 6). CD4 + Foxp3 + Treg cells and checkpoint molecules are essential for maintaining self-tolerance and preventing excessive immune responses, 43 but immune suppression can also be induced by an increase in Treg cells and the expression of PD-1 and LAG3 43,44 on T cells. The checkpoint molecules PD1, LAG3, and TIM3 have been shown to be hijacked by tumor cells to evade the host immune system in both mice and humans, and immunogenic tumor cells might induce the anergy of tumor-specific T cells by expressing these molecules on their surfaces, 22 which explains why some tumor cells could escape immune surveillance in this study.…”

An autologous humanized patient-derived-xenograft platform to evaluate immunotherapy in ovarian cancer

“…Clear cell carcinomas are generally less responsive to chemotherapy [35,36], but may have increased sensitivity to immunotherapy [37]. We therefore utilized an established PDX model derived from a mixed HGSOC with clear cell to test the activity of anti-PD-1 antibody therapy.…”