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Review
. 2020 Jul 2;12(7):1760.
doi: 10.3390/cancers12071760.

MHC Class I Downregulation in Cancer: Underlying Mechanisms and Potential Targets for Cancer Immunotherapy

Annelisa M Cornel  1 , Iris L Mimpen  1 , Stefan Nierkens  1   2
Affiliations
Review

MHC Class I Downregulation in Cancer: Underlying Mechanisms and Potential Targets for Cancer Immunotherapy

Annelisa M Cornel et al. Cancers (Basel). .

Abstract

In recent years, major advances have been made in cancer immunotherapy. This has led to significant improvement in prognosis of cancer patients, especially in the hematological setting. Nonetheless, translation of these successes to solid tumors was found difficult. One major mechanism through which solid tumors can avoid anti-tumor immunity is the downregulation of major histocompatibility complex class I (MHC-I), which causes reduced recognition by- and cytotoxicity of CD8+ T-cells. Downregulation of MHC-I has been described in 40-90% of human tumors, often correlating with worse prognosis. Epigenetic and (post-)transcriptional dysregulations relevant in the stabilization of NFkB, IRFs, and NLRC5 are often responsible for MHC-I downregulation in cancer. The intrinsic reversible nature of these dysregulations provides an opportunity to restore MHC-I expression and facilitate adaptive anti-tumor immunity. In this review, we provide an overview of the mechanisms underlying reversible MHC-I downregulation and describe potential strategies to counteract this reduction in MHC-I antigen presentation in cancer.

Keywords: MHC-I downregulation; adaptive immune involvement; antigen presentation; cancer immunotherapy; tumor immunogenicity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Major histocompatibility complex class I (MHC-I) antigen processing and presentation is a complex, multi-step process and can be dysregulated in cancer at multiple levels. APM = antigen processing machinery; ERAP = ER aminopeptidases; MHC-I = major histocompatibility complex I; TCR = T-cell receptor
Figure 2
Figure 2
NFkB-induced expression of MHC-I. Transcriptional activation of MHC-I heavy chain, but also other genes encoding for antigen processing machinery (APM) proteins, can be initiated by both the canonical (A) and non-canonical (B) NFkB pathway. IkB = inhibitors of kB; IKK = IkB kinase; NEMO = NF-kappa-B essential modulator; NIK = NFkB-inducing kinase; RIP-1 = receptor-interacting protein 1; TAK1 = TGF-β-activated kinase 1; TLR = toll-like receptor; TNFR = TNFα receptor; TRAF = TNF receptor-associated factor.
Figure 3
Figure 3
Interferon (IFN)-induced expression of MHC-I. Transcriptional activation of MHC-I heavy chain, but also other genes encoding for antigen processing machinery (APM) proteins, can be initiated by both the type II (A) and I (B) IFN pathway. GAS = gamma-activated site; IFNAR = IFNα receptor; IFNGR = IFNγ receptor; ISGF3 = IFN-stimulated gene factor 3; IRF = interferon regulatory factor; ISRE = interferon-stimulated response element; JAK = Janus Activated Kinase; STAT = signal transducer and activator of transcription; TYK2 = tyrosine kinase 2.
Figure 4
Figure 4
Potential therapeutic interference to boost MHC-I antigen presentation of tumors. Targetable negative pathway regulators are shown in red, (general groups of) compounds positively affecting pathway activation are shown in green.
See this image and copyright information in PMC

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