HLA‐G, HLA‐E, and IDO overexpression predicts a worse survival of Tunisian patients with vulvar squamous cell carcinoma

Abstract

Little is known about non‐classical HLA molecules in vulvar squamous cell carcinoma (VSCC). Because of the indoleamine‐2,3‐dioxygenase (IDO) immune tolerant role in association with HLA‐G, we evaluated the clinical and prognostic value of HLA‐G, HLA‐E, and IDO in VSCC. HLA‐G, HLA‐E, and IDO expression was determined by immunohistochemistry in VSCC and associated with clinicopathological parameters and disease outcome. These three molecules were highly represented in tumoral tissues vs healthy matched vulvar tissues (P = 0.0001). Significant differences in HLA‐G expression in stages, tumor size, tumor invasion depth, and resection margins subgroups were reported (P < 0.05). At 5 years, the cumulative survival rates was of 79.8% in patients with HLA‐Glow expression vs 12.5% in those with HLA‐Ghigh expression (P < 3 × 10−5). Similarly, patients with IDOhigh expression were at a significantly reduced overall survival (OS) and disease‐free survival (DFS) rates (P = 0.011 and 0.045, respectively). The overexpression of the three molecules together worsen survival rates of VSCC patients (OS: P = 0.000038, DFS: P = 0.000085). Altogether, our results showed that HLA‐G, HLA‐E, and IDO may represent novel candidate markers for patients' prognosis and potential targets for VSCC therapy.

HLA-G and Other Immune Checkpoint Molecules as Targets for Novel Combined Immunotherapies

“…Similarly, patients with vulvar squamous cell carcinoma (VSCC) showed a higher expression of HLA-G and IDO in cancer tissue than in surrounding normal tissue [ 95 ]. HLA-G expression was strongly associated with disease progression, whereas IDO expression correlated only with the extranodal spread of tumor.…”

“…More importantly, the clinical outcome of patients with a high expression of HLA-G or IDO was worse than those with a low expression of these molecules. Furthermore, patients showing a combined high expression of the two molecules, along with high HLA-E expression, display the worst clinical outcome, with very low survival rates [ 95 ]. Thus, in subjects affected by VSCC, HLA-G, and IDO, immune-suppressive functions are correlated, and the two molecules may co-operate in the inhibition of anti-tumor immune response, worsening the clinical outcome of patients.…”

HLA-G and single nucleotide polymorphism (SNP) associations with cancer in African populations: Implications in personal medicine

“…The increased expression of HLA-G in both solid and hematological tumors have been confirmed in various studies. Elevated expression of HLA-G has been observed in tumor lesions as membrane-bound HLA-G. For example, membrane-bound HLA-G has been found in the lesions of breast, 26 cervical, 69 endometrial, 11 , 70 vulva squamous cell 71 and lip squamous cell 72 cancers. The secretory form of HLA-G has also been found in body fluids like blood, ascites and saliva as sHLA-G. 19 , 24 , 73 Higher expression of HLA-G in cancerous cells than in pre-cancerous counterparts reflects an influence of HLA-G on cancer progression.…”

Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review

“…Finally, expression of indoleamine 2,3-dioxygenase (IDO) by VSCC cells is another potential mechanism of immune escape, since it restrains the proliferation of alloreactive T lymphocytes and of DCs through the local reduction of tryptophan, and may partially explain the immunological alterations present in these tumors. Furthermore, the IDO expression in VSCC cells is an independent negative prognostic factor in terms of OS [ 55 , 56 , 57 , 58 ].…”