Human leukocyte antigen G (HLA-G) mediates maternal-fetal immune tolerance. It is also considered an immune checkpoint in cancer since it may mediate immune evasion and thus promote tumor growth. HLA-G is, therefore, a potential target for immunotherapy. However, existing monoclonal antibodies directed against HLA-G lack sufficient specificity and are not suitable for immune checkpoint inhibition in a clinical setting. For this reason, it is essential that alternative approaches are explored to block the interaction between HLA-G and its receptors. In this review, we discuss the structure and peptide presentation of HLA-G, and its interaction with the receptors Ig-like transcript (ILT) 2, ILT4, and Killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4). Based on our findings, we propose three alternative strategies to block the interaction between HLA-G and its receptors in cancer immunotherapy: (1) prevention of HLA-G dimerization, (2) targeting the peptide-binding groove of HLA-G, and (3) targeting the HLA-G receptors. These strategies should be an important focus of future studies that aim to develop immune checkpoint inhibitors to block the interaction between HLA-G and its receptors for the treatment of cancer.

Background: Osteoarthritis (OA) severity as demonstrated by preoperative radiographs and preoperative pain play an important role in the indication for total knee arthroplasty (TKA). We investigated whether preoperative radiographic evidence of OA severity modified the effect of preoperative self-reported pain on postoperative pain and function 1 and 2 years after TKA for OA. Methods: Data from the Longitudinal Leiden Orthopaedics Outcomes of Osteoarthritis Study (LOAS), a multicenter cohort study on outcomes after TKA, were used. OA severity was assessed radiographically with the Kellgren and Lawrence (KL) score (range, 0 to 4). Pain and function were evaluated with the Knee injury and Osteoarthritis Outcome Score (KOOS). After adjustment for body mass index (BMI), age, sex, and the Mental Component Summary scores from the Short Form-12, multivariate linear regression analyses with an interaction term between the preoperative KL score and preoperative pain were performed. Results: The study included 559 patients. The preoperative KL score was independently associated with 1-year postoperative pain and function (β = 5.4, 95% confidence interval [CI] = 1.4 to 9.4, and β = 7.7, 95% CI = 3.2 to 12.2), while preoperative pain was associated only with postoperative pain (β = 0.3, 95% CI = 0.1 to 0.6) and not with postoperative function (β = 0.2, 95% CI = −0.2 to 0.5). Comparable associations were found between 2-year postoperative pain and KL score (β = 8.0, 95% CI = 3.2 to 12.7) and preoperative pain (β = 0.5, 95% CI = 0.1 to 0.8) and between 2-year postoperative function and KL score (β = 7.7, 95% CI = 3.2 to 12.2). The study showed a trend toward the KL score modifying the effect of preoperative pain on 1-year postoperative pain (β = −0.1, 95% CI = −0.1 to 0.0) and 2-year postoperative pain (β = −0.1, 95% CI = −0.2 to 0.0) and on 1 and 2-year function (β = −0.1, 95% CI = −0.2 to 0.0 for both), with the effect of preoperative pain on postoperative pain and function seeming to become less important when there was radiographic evidence of greater preoperative OA severity. Conclusions: Patients with less pain and higher KL grades preoperatively had better function and pain outcomes 1 and 2 years after TKA. However, the effect of preoperative pain on the postoperative outcomes seems to become less important when the patient has radiographic evidence of more severe OA. We believe that analysis of the severity of preoperative pain is an important proxy for optimal postoperative patient outcome. Level of Evidence: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

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.