HLA-dependent tumour development: a role for tumour associate macrophages?

Abstract

HLA abnormalities on tumour cells for immune escape have been widely described. In addition, cellular components of the tumour microenvironment, in particular myeloid derived suppressor cells (MDSC) and alternatively activated M2 tumour-associated macrophages (TAMs), are involved in tumour promotion, progression, angiogenesis and suppression of anti-tumour immunity. However, the role of HLA in these activities is poorly understood. This review details MHC class I characteristics and describes MHC class I receptors functions. This analysis established the basis for a reflection about the crosstalk among the tumour cells, the TAMs and the cells mediating an immune response.The tumour cells and TAMs exploit MHC class I molecules to modulate the surrounding immune cells. HLA A, B, C and G molecules down-regulate the macrophage myeloid activation through the interaction with the inhibitory LILRB receptors. HLA A, B, C are able to engage inhibitory KIR receptors negatively regulating the Natural Killer and cytotoxic T lymphocytes function while HLA-G induces the secretion of pro-angiogenic cytokines and chemokine thanks to an activator KIR receptor expressed by a minority of peripheral NK cells. The open conformer of classical MHC-I is able to interact with LILRA receptors described as being associated to the Th2-type cytokine response, triggering a condition for the M2 like TAM polarization. In addition, HLA-E antigens on the surface of the TAMs bind the inhibitory receptor CD94/NKG2A expressed by a subset of NK cells and activated cytotoxic T lymphocytes protecting from the cytolysis.Furthermore MHC class II expression by antigen presenting cells is finely regulated by factors provided with immunological capacities. Tumour-associated macrophages show an epigenetically controlled down-regulation of the MHC class II expression induced by the decoy receptor DcR3, a member of the TNFR, which further enhances the M2-like polarization. BAT3, a positive regulator of MHC class II expression in normal macrophages, seems to be secreted by TAMs, consequently lacking its intracellular function, it looks like acting as an immunosuppressive factor.In conclusion HLA could cover a considerable role in tumour-development orchestrated by tumour-associated macrophages.

Overcoming barriers to effective immunotherapy: MDSCs, TAMs, and Tregs as mediators of the immunosuppressive microenvironment in head and neck cancer

“…TAMs also express the checkpoint ligands CD80/86 (B7-1/2) that inhibit TILs through binding CTLA4 [77]. In some cancer models, surface expression of specific MHC class I proteins can activate or suppress effector immune cells, with macrophage expression of less common HLA-G and E demonstrating ability to suppress T and NK cell function [78]. TAMs also secrete immunosuppressive cytokines IL-1β, IL-6, IL-10, and TGFβ [74].…”

Aberrant DNA methylation impacts gene expression and prognosis in breast cancer subtypes

“…Noteworthy, we showed that the high expression of another immune‐related gene, HLA‐A , was associated with prolonged survival in patients with ER−/HER2− tumors. HLA‐A belongs to the classical HLA class I (HLA‐I) family, which modulates the function of the tumor‐immune microenvironment, having a key role in cancer development orchestrated by tumor‐associated macrophages and immune recognition of cancer cells by cytotoxic T lymphocytes (CTLs) . The downregulation of HLA‐I expression by epigenetic silencing has been involved in tumor escape from immune surveillance, and has been reported in several types of human cancer, including BC .…”

HLA-E coding and 3′ untranslated region variability determined by next-generation sequencing in two West-African population samples

“…Among these, we may find the derivative gpUL40 leader sequence of two human cytomegalovirus (HCMV) strains, peptides derived from the human immunodeficiency virus (HIV) gag protein, the Epstein-Barr virus (EBV) BZLF-1 protein, the influenza matrix protein and the Hepatitis C virus (HCV) core protein [7][8][9]. The binding of HLA-E with these viral peptides can trigger an escape mechanism of the innate immune response by inhibiting the NK cell-mediated cytotoxicity but it may also prompt adaptive immune responses by the activation of cytotoxic T activity [7][8][9][10][11][12][13]. Whereas HLA-E expression usually occurs at low levels [9], this molecule is widely http://dx.doi.org/10.1016/j.humimm.2015.06.016 0198-8859/Ó 2015 American Society for Histocompatibility and Immunogenetics.…”