A Critical Assessment of the Association between HLA-G Expression by Carcinomas and Clinical Outcome

Abstract

Human leukocyte antigen-G (HLA-G) conveys immunological tolerance at the maternal-foetal interface. HLA-G expression by tumour cells may also play such a role, resulting in tumour immune evasion, making HLA-G a potential target for immunotherapies. The aim of this review was to determine to what extent it is justified that HLA-G expression is considered as a target for immune checkpoint inhibiting therapy by critically assessing the association between HLA-G expression by carcinomas and clinical outcome of patients. The used HLA-G-detecting mAb, HLA-G quantification methods and statistically significant HLA-G-associated clinicopathological parameters are discussed. Tumour HLA-G expression correlated with poor clinical outcome in breast, esophageal, gastric and hepatocellular carcinoma patients. Tumour HLA-G expression was not associated with clinical outcome in ovarian and oral carcinoma patients. Cervical, colorectal, lung, and pancreatic carcinoma patients presented discrepant and therefore inconclusive results regarding the association between tumour HLA-G expression and clinical outcome. These disparities might partly be the result of differences in the methodological approach to quantify HLA-G expression between studies. Therefore, implementation of universal methodological procedures is strongly advised. Overall, HLA-G expression did not univocally result in poor clinical outcome of carcinoma patients. This implies that tumour HLA-G expression is not necessarily part of an inhibited tumour-immune response and tumour progression. Consequently, it remains elusive whether HLA-G expression by carcinomas functions as an immune checkpoint molecule affecting a tumour-immune response. It may also reflect derailed control of gene expression in tumours, with no real functional consequences.

HLA-G: Too Much or Too Little? Role in Cancer and Autoimmune Disease

“…It is now widely accepted that HLA-G is a critical marker of immunotolerance in cancer immune evasion and is strongly associated with disease progress and prognosis in cancer patients. However, not all published works are equally consistent and, although they show HLA-G expression in cancer, do not allow to correlate HLA-G with certain types of cancer (81).…”

“…The other problem lies in the methodological approaches employed. The vast majority of HLA-G detection studies use immunohistochemistry as the main method, but each laboratory uses different antibodies and variable experimental conditions (incubation times, antibody concentration, etc), even when analyzing the same type of tumor (81)(82)(83). In addition, some of these antibodies used, such as the 4H84 clone, appear to be poorly specific for HLA-G detection (84).…”

Oxidative Stress-Related lncRNAs Are Potential Biomarkers for Predicting Prognosis and Immune Responses in Patients With LUAD

“…The loss of HLA also occurs in LUAD, and the proportion of occurrence is not low ( Dejima et al, 2021 ). But at the same time, we also noticed that the research of van de Water et al (2021 ) showed that the expression level of HLA-G was inconsistent with the prognosis of lung cancer, but the prognosis and HLA-G level of patients with breast cancer, esophageal cancer, gastric cancer, and hepatocyte maintained a good correlation. This is in common with our findings and contradicts them, implying that the mutational diversity of HLA molecules has the value for further study.…”

What Inhibits Natural Killers’ Performance in Tumour

“…HLA-G interacts with NK cell killer Ig-like receptors (KIRs), resulting in the inhibition of NK cells [164]. Consistently, HLA-G expression in various malignancies was associated with tumour escaping immunosurveillance and was also involved in the mechanism of metastasis, leading to poor clinical outcomes [165].…”