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

Fabio Morandi,Irma Airoldi

doi:10.3390/ijms23062925

Fabio Morandi, Irma Airoldi

Open Access

https://doi.org/10.3390/ijms23062925

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Abstract

HLA-G is an HLA-class Ib molecule that is involved in the establishment of tolerance at the maternal/fetal interface during pregnancy. The expression of HLA-G is highly restricted in adults, but the de novo expression of this molecule may be observed in different hematological and solid tumors and is related to cancer progression. Indeed, tumor cells expressing high levels of HLA-G are able to suppress anti-tumor responses, thus escaping from the control of the immune system. HLA-G has been proposed as an immune checkpoint (IC) molecule due to its crucial role in tumor progression, immune escape, and metastatic spread. We here review data available in the literature in which the interaction between HLA-G and other IC molecules is reported, in particular PD-1, CTLA-4, and TIM-3, but also IDO and TIGIT. Clinical trials using monoclonal antibodies against HLA-G and other IC are currently ongoing with cancer patients where antibodies and inhibitors of PD-1 and CTLA-4 showed encouraging results. With this background, we may envisage that combined therapies using antibodies targeting HLA-G and another IC may be successful for clinical purposes. Indeed, such immunotherapeutic protocols may achieve a better rescue of effective anti-tumor immune response, thus improving the clinical outcome of patients.

Highlights

HLA-G is a non-classical major histocompatibility complex (MHC) class I molecule with immune-suppressive properties
Eight clinical trials are currently treating NB patients with antibodies against immune checkpoint (IC) molecules: three of them are using Nivolumab, Dostarlimab or Pembrolizumab, four of them are based on the administration of Ipilimumab, and the last one is employing Enoblituzumab
Several studies in the last years suggested that HLA-G is part of an immunosuppressive loop that involved other IC molecules, in particular programmed cell death receptor (PD)-1 and cytotoxic T lymphocytesassociated protein (CTLA)-4

Summary

Introduction

HLA-G is a non-classical MHC class I molecule with immune-suppressive properties. It belongs to the group of HLA-class Ib molecules that includes HLA-E, -F, and H. ITIM recruit the protein tyrosine phosphatase SHP-1 (Src homology 2 domain containing phosphatase 1), which de-phosphorylate signaling proteins involved in early events triggered by stimulatory receptors [16] Another HLA-G receptor is KIR2DL4, which is expressed on NK cells and a subset of T lymphocytes; it recognizes all HLA-G isoforms through the α1 domain [17–19]. In the end, HLA-G contributes to the metastatic spread and to the evolution of aggressive tumor cells in different solid and hematological tumors [12,30,61] Taken together, all these features highlight the role of HLA-G as an immune checkpoint (IC) molecule and as a novel therapeutic target for cancer immunotherapy, as recently discussed [62]. On the basis of these observations, we discuss future possible therapeutic strategies based on the combination of (i) blocking antibodies against HLA-G or its receptors and (ii) blocking antibodies specific for other IC molecules, with the aim of fully restoring anti-tumor immune response

Immune Checkpoint Molecules

HLA-G and PD-1/PD-L1 Axis

CTLA-4 and TIM-3

HLA-G and Other IC in Pediatric Solid Tumors

Findings

Conclusions