Intercellular transfer of HLA‐G: its potential in cancer immunology

Abstract

Intercellular protein transfer between cancer cells and immune cells is a very common phenomenon that can affect different stages of host antitumor immune responses. HLA‐G, a non‐classical HLA class I antigen, has been observed to be widely expressed in various malignancies, and its immune‐suppressive functions have been well recognised. HLA‐G expression in cancer cells can directly mediate immune tolerance by interacting with inhibitory receptors such as ILT2 and ILT4 expressed on immune cells. Moreover, a network of multiple directional intercellular transfers of HLA‐G among cancer cells and immune cells through trogocytosis, exosomes and tunnelling nanotubes provides malignant cells with an alternative ploy for antigen sharing and induces more complex heterogeneity, to modulate immune responses, ultimately leading to immune evasion, therapy resistance, disease progression and poor clinical outcome. Herein, we discuss the relative aspects of the intercellular transfer of HLA‐G between tumor cells and immune cells and its potential use in tumor immunology research and translational cancer therapy.

The Role of HLA-G in Human Papillomavirus Infections and Cervical Carcinogenesis

“…The HLA-G gene consists of eight exons, seven introns, a 5 ′ upstream regulatory region (URR) that extends at least 1,400 bp from the initial ATG start codon, and a 3 ′ untranslated region (UTR), with a total length of 6,000 bp (12,17). It is widely accepted that the HLA-G primary transcript is alternatively spliced into seven mRNAs, which encode four membrane-bound (HLA-G1, -G2, -G3, -G4) and three soluble (HLA-G5, -G6, -G7) protein isoforms (18,19).…”

“…Functionally, HLA-G has comprehensive immunosuppressive properties exerted in multiple steps to weaken antitumor immune responses by acting on immune cells through its inhibitory receptors: ILT2(CD85j/LILRB1), ILT4(CD85d/LILRB2), and KIR2DL4(CD158d) (11,12,(55)(56)(57)(58)(59) (Figure 1). HLA-G inhibits the cytolytic function of natural killer (NK) cells (60,61), cytotoxic T lymphocyte (CTL)mediated cytolysis (62), macrophage-mediated cytotoxicity (63), allo-proliferative response of CD4 + T cells (64,65), maturation and function of dendritic cells (DCs) or B lymphocytes (66)(67)(68)(69), stimulation of antigen-presenting cells (APCs) to secrete functional cytokines TGF-β and IL-10, and induction of apoptosis of CD8 + T cells and CD8 + NK cells (70,71).…”

“…HLA-G has been termed "non-classical" due to its low frequency of polymorphisms, restricted tissue distribution and immunoinhibitory properties, which are different from the properties of classical HLA-class I molecules (10,11). It has become increasingly evident that the HLA-G molecule is involved in modulating both innate and adaptive immune responses and in promoting immune escape in various types of cancers (10)(11)(12)(13) and infectious diseases (14)(15)(16). However, to date, the possibility that HLA-G gene polymorphisms and/or protein expression affecting HPV infection persistence and cervical cancer risk remains to be explored.…”

The role of trogocytosis in immune surveillance of Hodgkin lymphoma

“…27 HLA-G, an immunosuppressive molecule, has been reported to be transferred among tumor cells and immune cells, leading to a suppressive tumor environment and a dampened anti-tumor immunity. 28 Therefore, the effect of trogocytosis on immune responses needs to be analyzed on a case-by-case basis. 21 Below, we will summarize recent results on the effect of trogocytosis on HL.…”

Inhibitory checkpoints in human natural killer cells: IUPHAR Review 28

“…In addition, several approaches have been developed to block the HLA‐G/ILT signalling pathway, which take into account also the different mechanism regulating HLA‐G surface expression. These approaches include HLA‐G antagonists, blocking antibodies against HLA‐G or its receptors, siRNA, inhibition of its intercellular transfer and HLA‐G as target for drug delivery (Li et al, 2017; Lin & Yan, 2019; Zhang et al, 2014). Therefore, KIRs and HLA‐G may also represent promising targets for combined therapy.…”