Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation

Abstract

Major histocompatibility class I (MHC I) molecules bind peptides derived from a cell's expressed genes and then transport and display this antigenic information on the cell surface. This allows CD8 T cells to identify pathological cells that are synthesizing abnormal proteins, such as cancers that are expressing mutated proteins. In order for many cancers to arise and progress, they need to evolve mechanisms to avoid elimination by CD8 T cells. MHC I molecules are not essential for cell survival and therefore one mechanism by which cancers can evade immune control is by losing MHC I antigen presentation machinery (APM). Not only will this impair the ability of natural immune responses to control cancers, but also frustrate immunotherapies that work by re-invigorating anti-tumor CD8 T cells, such as checkpoint blockade. Here we review the evidence that loss of MHC I antigen presentation is a frequent occurrence in many cancers. We discuss new insights into some common underlying mechanisms through which some cancers inactivate the MHC I pathway and consider some possible strategies to overcome this limitation in ways that could restore immune control of tumors and improve immunotherapy.

Pan-Cancer Analysis of DNA Methylation Identifies Genes and Biological Functions Associated with Overall Survival

“…This may be the case, for example, in the HLA locus. Within this locus our analysis highlighted class I MHC genes, hypermethylation of which has previously been reported to impair anti-tumor immune responses in multiple cancer types by reducing presentation of tumor-specific peptides [31]. We also found some nearby class II MHC genes had methylation associated with shorter survival.…”

Molecular Mechanisms of Drug Resistance in Glioblastoma

“…Another reason for immune evasion is the lack of recognition of tumor cells by T lymphocytes due to inadequate or low presentation of antigens. This is often due to the fact that cancer cells often lose class I and/or II histocompatibility antigens required for antigen presentation [70]. To stimulate the differentiation of precursor T cells to cytotoxic T lymphocytes, it may be necessary to express not only antigens for binding to T cell receptors by tumor cells, but also ligands to ensure the adhesion of T cells to tumor cells for their co-stimulation [71].…”

MHC Class I Deficiency in Solid Tumors and Therapeutic Strategies to Overcome It

“…Downregulation or loss of classical MHC-I molecules is frequently observed and is considered the most common mechanism of tumor immune escape, as it leads to poor tumor recognition and limited killing by cytotoxic T cells. In contrast, tumors infiltrated by CD8 T cells often demonstrate higher MHC-I expression compared to the adjacent tissue, an increase that has been linked mechanistically to IFNγ secreted by activated T cells in the tumor microenvironment [40,48]. While the significance of loss or downregulation of MHC-I expression in tumors has long been recognized [48][49][50][51], the precise molecular mechanisms underlying this loss have only recently been fully explored.…”

“…These unique immunoproteasome components replace the standard β1, β2 and β5 proteasome subunits to enhance the generation of MHC-I-compatible peptides [45]. This effect is mediated by several transcription factors, including the p50 and p65 subunits of the nuclear factor kappa-light-chain-enhancer of activated B cells (NK-kB) and interferon regulatory factor 1 (IRF1) that bind to the Enhancer A and the interferon-stimulated response element (ISRE), respectively, in the MHC-I promoter to stimulate the expression of MHC-I heavy chains and the APM genes (Figure 1) [40,46]. In addition, IFNγ stimulates expression of NLRC5 that assembles the CITA enhanceosome with transcription factors binding to W/S, X1, X2 and Y1 boxes in the MHC-I promoter (Figure 1) [47].…”