In vivo evidence that secretion of HLA‐G by immunogenic tumor cells allows their evasion from immunosurveillance

Abstract

Human leukocyte antigen‐G (HLA‐G) expression by tumors has been evidenced in numerous malignancies in association with poor prognosis and resistance to immunotherapy in humans. Particularly, soluble form of HLA‐G was measured at high concentrations in malignant effusions and plasma from cancer patients, and inhibits antitumor immune cells in vitro through interaction with immunoglobulin‐like transcript (ILT) receptors. Nevertheless, in vivo study demonstrating that HLA‐G secretion by tumor cells allows their escape from immunosurveillance remained to be established. Despite nondescribed murine homolog, direct functional interaction of HLA‐G with murine paired immunoglobulin‐like receptor (PIR)‐B, ortholog of human ILT receptors, enables to investigate its role in vivo. Immunocompetent mice were injected either with syngeneic tumor cells co‐expressing HLA‐G5, the main soluble HLA‐G isoform, and the conformation stabilizer human β2‐microglubulin (hβ2m), or with hβ2m+HLA‐G5− tumor cells. hβ2m expressed at both tumor cell surface acted as a tumor antigen triggering a specific humoral response. Interestingly, although hβ2m+HLA‐G5− tumors were rejected, secreted HLA‐G5 provided hβ2m+HLA‐G5+ tumors a protection against hβ2m‐elicited immune rejection, enabling such immunogenic tumors to grow similarly to a poorly immunogenic tumor. HLA‐G5 tumor expression was associated with local and peripheral immunosuppression, characterized by dampened anti‐hβ2m B‐cell response, quantitative and functional T‐and B‐cell defects, accumulation of myeloid‐derived suppressor cells able to inhibit T‐cell proliferation and reduced T‐ and B‐cell tumor infiltrate. Our study provides the first in vivo proof that soluble HLA‐G counteracts tumor rejection and reinforces the importance to consider HLA‐G as a promising target to optimize current cancer immunotherapies.

Human Leukocyte Antigen-G (HLA-G) Expression in Cancers: Roles in Immune Evasion, Metastasis and Target for Therapy

“…HLA-G can directly inhibit immune cell function through receptor binding and/or through trogocytosis and impairment of chemotaxis (15,16); moreover, HLA-G can render tumor cells with a higher invasive, metastatic potential and an unfavorable prognosis in tumor patients, indicating that HLA-G expression has multiple effects including promoting tumor cells to escape immune surveillance and enhancing their metastasis during the progression of malignancies (17)(18)(19). Therefore, the role of HLA-G in malignancies has gained considerable clinical interest for the possibility of exploiting it as a molecular biomarker and a therapeutic target.…”

Expansion of HLA-G-Expressing Myeloid-Derived Suppressor Cells in Patients with Chronic Hepatitis B Virus Infection

“…In the context of MDSCs, interaction between HLA-G and murine cell receptor PIR-B (homology with the human ILTs) could expand the population of CD11 b+ Gr 1+ PIR-B+ or CD11b + Ly6G + MDSCs, which could decrease NK cytotoxic activity [19,20]. Moreover, in ILT-2 transgenic mice, HLA-G has been found to induce the emergence of CD11b + Gr1 + MDSCs with an enhanced suppressive activity and directly involved in the prolongation of allogeneic skin graft survival [34].…”

“…The murine receptor paired immunoglobulin like receptor-B (PIR-B), a homology to human ILTs, can bind to HLA-G [18]. Previous findings had recognized that through binding to the PIR-B expressed on MDSCs, and HLA-G has been found with the capability to contribute the expansion and suppressive functions of MDSCs [19,20].…”

Potential Roles of HLA-G and MDSCs in Virus Infection

“…Recent studies showed that interaction between HLA-G and PIR-B could expand the population of CD11b + Gr1 + PIR-B + MDSCs in an immunocompetent HLA-G1 + M8 (a human melanoma cell line) tumor-bearing mouse model, which could decrease NK cytotoxic activity [5]. In another study, in a mouse model with murine mammary 4T1 cell line, HLA-G5 was observed to favor the CD11b + Ly6G + mice G-MDSC expansion with binding to PIR-B [19]. Moreover, in ILT-2 transgenic mice, HLA-G has been found to induce the emergence of CD11b + Gr1 + MDSCs with an enhanced suppressive activity and directly involved in the prolongation of allogeneic skin graft survival [20].…”