Loss of Major Histocompatibility Complex Class I, CD8+ Tumor-infiltrating Lymphocytes, and PD-L1 Expression in Ovarian Clear Cell Carcinoma

Abstract

Ovarian clear cell carcinoma (OCCC), a chemoresistant ovarian cancer, shows a modest response to anti–programmed death-1/programmed death ligand-1 (PD-1/PD-L1) therapies. The effects of anti-PD-1/PD-L1 therapies rely on cytotoxic T-cell response, which is triggered by antigen presentation mediated by major histocompatibility complex (MHC) class I. The loss of MHC class I with simultaneous PD-L1 expression has been noted in several cancer types; however, these findings and their prognostic value have rarely been evaluated in OCCC. We collected data from 76 patients with OCCC for clinicopathologic analysis. Loss of MHC class I expression was seen in 44.7% of the cases including 39.3% to 47.4% of the PD-L1+ cases and was associated with fewer CD8+ tumor-infiltrating lymphocytes (TILs). PD-L1 positivity was associated with a higher number of CD8+ TILs. Cox proportional hazard models showed that high (≥50/mm2) CD8+ TILs was associated with shorter disease-specific survival (hazard ratio [HR]=3.447, 95% confidence interval [CI]: 1.222-9.720, P=0.019) and overall survival (HR=3.053, 95% CI: 1.105-8.43, P=0.031). PD-L1 positivity using Combined Positive Score was associated with shorter progression-free survival (HR=3.246, 95% CI: 1.435-7.339, P=0.005), disease-specific survival (HR=4.124, 95% CI: 1.403-12.116, P=0.010), and overall survival (HR=4.489, 95% CI: 1.553-12.972, P=0.006). Loss of MHC class I may contribute to immune evasion and resistance to anti-PD-1/PD-L1 therapies in OCCC, and CD8+ TILs and PD-L1 positivity using Combined Positive Score may have a negative prognostic value.

Development and validation of a novel anoikis-related gene signature for predicting prognosis in ovarian cancer

“…Furthermore, down-regulation of β-Catenin has been shown to inhibited tumor growth and peritoneal metastasis in OC tumor model by stopping the formation of OC spheroids, which protected tumor cells from anoikis [52]. In contrast, LRisk subgroup was associated with antitumor-related pathways, primarily those related to immune activation, such as interferon-gamma, T cell Cox proportional hazards model shows that highly infiltrated CD8+ TILs are associated with shorter disease-specific survival and overall survival [53].…”

“…Different immune cells play different roles in the development of ovarian cancer. Cox proportional hazards model shows that highly infiltrated CD8+ TILs are associated with shorter disease-specific survival and overall survival [ 53 ].…”

Exploring the Potential of Natural Killer Cell-Based Immunotherapy in Targeting High-Grade Serous Ovarian Carcinomas

“…Both OVCAR8 and CAOV3 had minimal expression of MHC-class I and were highly killed by NK cells when compared to the other tumor lines [ 44 ]. The down-modulation or loss of MHC-class I and class II has been reported in ovarian carcinoma [ 105 , 106 , 107 , 108 , 109 ] and is one of the factors contributing to escape by the immune system [ 110 ]. Increased expression levels of MHC-class I and class II in ovarian cancer correlate with increased numbers of tumor-infiltrating lymphocytes, an increased response to PD1/PDL1 therapy, better prognosis, and the prolonged life of cancer patients [ 108 , 109 , 111 , 112 ].…”

Landscapes and mechanisms of CD8+ T cell exhaustion in gastrointestinal cancer

“…Mechanisms mediated by cancer cells include loss of MHC expression, loss of antigen, loss or defect in antigen presentation, or expression of inhibitory receptor ligands. Loss of MHC class I expression of PD-L1 or other ICPs has been noted in many cancer types ( 36 ). expression of most components of the MHC I antigen presentation pathway is nonessential for cell survival and therefore is usually loss of function in cancer cells, leading to T cell depletion.…”