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.

Keywords: HLA‐G; cancer; exosome; trogocytosis; tunnelling nanotubes.

Figure 1

Immune suppression induced by intercellular transfer of tumor HLA‐G. (A) HLA‐G⁻ cancer cells can acquire HLA‐G molecules from HLA‐G⁺ cancer cells and become HLA‐G^acq+ cancer cells via trogocytosis (a), exosomes (b) and tunnelling nanotubes (c). (B) Immune cells can acquire HLA‐G molecules from HLA‐G⁺ cancer cells and become HLA‐G^acq+ immune cells, such as HLA‐G^acq+ CD4⁺ T cells, HLA‐G^acq+ CD8⁺ T cells, HLA‐G^acq+ NK cells and HLA‐G^acq+ CD14⁺ monocytes. (C) Immune cells can acquire HLA‐G molecules from HLA‐G⁺ immune cells and become HLA‐G^acq+ immune cells such as HLA‐G^acq+ CD4⁺ T cells, HLA‐G^acq+ CD8⁺ T cells and HLA‐G^acq+ monocytes. Immune cell functions are suppressed after acquiring HLA‐G via different intercellular transfer processes, such as the inhibition of proliferation and cytotoxicity, and induction of suppressive NK cells in HLA‐G^acq+ NK cells; the inhibition of proliferation and induction of Treg and anergic T cells in HLA‐G^acq+ T cells, and the impairment of the maturation of HLA‐G^acq+ dendritic cells.

Figure 2

Multiple levels of HLA‐G‐targeted cancer immunotherapy strategies. Using (a) potential inhibitors to impair the formation and process of trogocytosis, (b) exosomes and (c) tunnelling nanotubes, which transport HLA‐G to other cells, (d) post‐transcriptional RNA interference to down‐regulate HLA‐G transcription, (e) specific blocking antibodies to block either HLA‐G or receptor ILTs, (f) HLA‐G antibodies conjugated with antitumor drugs to target HLA‐G‐positive cancer cells, (g) HLA‐G‐derived immunogenic peptides to activate the T‐cell immune response and (h) target HLA‐G⁺ tumor cells to develop drug delivery systems.