Relationship between Microsatellite Instability, Immune Cells Infiltration, and Expression of Immune Checkpoint Molecules in Ovarian Carcinoma: Immunotherapeutic Strategies for the Future

Abstract

Ovarian cancer has the worst prognosis among gynecological cancers. Thus, new ovarian cancer treatment strategies are needed. Currently, immune checkpoint inhibitors such as anti-PD-1/PD-L1 antibody are attracting attention worldwide. The Food and Drug Administration approved the use of the PD-1 antibody pembrolizumab for solid cancers with microsatellite instability (MSI)-H or mismatch repair (MMR) deficiency in 2017. However, few studies on ovarian carcinoma have evaluated the relationship among MSI status, lymphocyte infiltration into the tumor, and the expression of immune checkpoint molecules by histologic type. We evaluated the expression of MMR proteins, tumor-infiltrating lymphocytes (CD8+), and immune checkpoint molecules (PD-L1/PD-1) by immunohistochemistry in 136 ovarian cancer patients (76, 13, 23, and 24 cases were high-grade serous, mucinous, endometrioid, and clear cell carcinoma, respectively) to investigate the effectiveness of immune checkpoint inhibitors. Only six cases (4.4%) had loss of MMR protein expression. There was no significant relationship between MSI status and age (p = 0.496), FIGO stage (p = 0.357), initial treatment (primary debulking surgery [PDS] or neoadjuvant chemotherapy) (p = 0.419), residual tumor after PDS or interval debulking surgery (p = 0.202), and expression of CD8 (p = 0.126), PD-L1 (p = 0.432), and PD-1 (p = 0.653). These results suggest that only a small number of MSI cases in ovarian cancer can be effectively treated with immune checkpoint inhibitor monotherapy. Therefore, to improve the prognosis of ovarian carcinoma, a combination therapy of immune checkpoint inhibitors and other anticancer drugs is necessary.

Characteristics of Subtypes Within Microsatellite Instability-high Gastric Cancer Based on a Gene Signature Related to Immune Microenvironment Components

“…MSI-H tumors were often associated with defects in DNA mismatch repair, which led to higher levels of genetic mutations and neoantigens and eventually caused an active antitumor immune microenvironment; this is generally believed to improve the immunotherapy e cacy [25][26][27]. Our study found that the tumor mutation load and intratumoral heterogeneity level were comparable between the subgroups.…”

DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

“…Tumor profiling for MSI serves as a measure for the personalized management of several cancers [ 116 , 117 ]. Regarding OvC, MSI occurs in a limited percentage of the tumors (2–20%) and affects predominantly endometrioid (19.2%), mucinous (16.9%), clear cell (11.2%), and serous (7.9%) subtypes [ 118 , 119 ]. Both endometrioid and clear cell subtypes with MSI show increased levels of tumor-infiltrating lymphocytes and thus may be susceptible to immune checkpoint inhibitor monotherapy [ 120 ].…”

The relation of CD3, CD4, CD8 and PD-1 expression with tumor type and prognosis in epithelial ovarian cancers

“…Although the mechanism is uncertain, it can activate M1 macrophages through interleukin-12 or interferon gamma secretion [27]. In studies conducted in different years, the presence of intraepithelial CD4 + T-lymphocytes has been associated with better survival [6,[28][29][30]. In our study, the presence of stromal CD4 + T-lymphocyte was more common in late stage patients than in the early stage.…”

“…Antibodies specifically blocking PD-1 became available for melanoma in 2014 and went into use for non-small cell lung cancer (NSCLC) in the United States, the European Union and Japan, in 2015, primarily approved by the Food and Drug Administration (FDA) [31]. The FDA approved the use of anti-PD-1 antibody pembrolizumab for solid cancers with microsatellite instability (MSI)-H or mismatch repair (MMR) deficiency in May 2017 [6]. Currently, two classes of FDA-approved immunotherapy for clinical use are PD-1 / PD-L1 and CTLA-4 inhibitors [32].…”

“…New treatment strategies are needed as current treatment methods are not sufficient to increase the survival rate of patients with ovarian cancer. Nowadays, there are many ongoing clinical studies on the effectiveness of ICIs in ovarian cancer [6].…”