Role of non-classical MHC class I molecules in cancer immunosuppression

Abstract

Growing neoplasms employ various mechanisms to evade immunosurveillance. The expression of non-classical MHC class I molecules by both immune and malignant cells in the tumor microenvironment constitute of the strategies used by tumors to circumvent the cytotoxic activity of effector cells of the immune system. The overexpression of HLA-G, -E, and -F is a common finding across a variety of malignancies. However, while the presence of HLA-G and HLA-E has been recently correlated with poor clinical outcome, information on the clinicopathological significance of HLA-F is limited. In the present review, we summarize studies on non-classical MHC class I molecules with special emphasis on their role in the modulation of anticancer immune responses.

Keywords: NK cells; T cells; antigen presentation; cancer; immunomodulation; non-classical MHC class I molecules.

Figure 1. Immunological mechanisms of HLA-G-mediated immunosuppression by cancer cells. Cancer cells expose HLA-G molecules (in green) on their surface or secrete it (HLA-G5), inducing the apoptotic demise of effector cells. The transfer of HLA-G-containing membranes to T and natural killer (NK) cells renders them immunosuppressive. The binding of HLA-G1 to inhibitory receptors such as ILT-2 and ILT-4 mediated immunosuppressive mechanisms in a variety of immune cells. ARG-1, arginase 1; iDC, immature dendritic cell; IFNγ, interferon γ; IL-10, interleukin-10; iNOS, inducible nitric oxide synthase; TGFβ, transforming growth factor β; Tol DC, tolerogenic dendritic cell.

Figure 2. Immunological mechanisms of HLA-E-mediated immunosuppression by cancer cells. In Cancer cells expose HLA-G (in green) and HLA-E (in red) molecules of their surface. The secretion of HLA-E induces apoptosis in immune effectors. Moreover, in the presence of interferon γ (IFNγ), HLA-G and HLA-E molecules are expressed at increased levels on the surface of both cancer cells and CD4⁺ T lymphocytes. The binding of HLA-E expressed on CD4⁺ T cells to the T-cell receptor (TCR) of CD4⁺ T lymphocytes can induce the differentiation of the latter into regulatory CD8⁺ T cells (CD8⁺ reg). The binding of HLA-E to NKG2A inhibits the cytotoxic functions of CD8⁺ T lymphocytes and NK cells.