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Cited by 1,077Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

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Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation

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Dhatchinamoorthy, Karthik, Colbert, Jeff D., Rock, Kenneth L.·2021·Frontiers in Immunology
DOI 10.3389/fimmu.2021.636568PMC PMC7986854
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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.

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Figures

Figure 1 The MHC class I antigen presentation pathway. Cellular proteins are hydrolyzed by the ubiquitin-proteosome pathway into oligopeptides, which are subsequently transported into endoplasmic reticulum through the TAP transporter. In the ER these peptides may be further trimmed by ERAP1 and then peptides of the right length and sequence bind to MHC I molecules with the help of Tapasin in a peptide-loading complex containing Tapasin, TAP, calreticulim, and ERP57, or the with the help of TAPBPR. After MHCI molecules bind peptide, they are transported to the cell surface for display to CD8+ T cells.
Figure 1 The MHC class I antigen presentation pathway. Cellular proteins are hydrolyzed by the ubiquitin-proteosome pathway into oligopeptides, which are subsequently transported into endoplasmic reticulum through the TAP transporter. In the ER these peptides may be further trimmed by ERAP1 and then peptides of the right length and sequence bind to MHC I molecules with the help of Tapasin in a peptide-loading complex containing Tapasin, TAP, calreticulim, and ERP57, or the with the help of TAPBPR. After MHCI molecules bind peptide, they are transported to the cell surface for display to CD8+ T cells.CC BY · PubMed Central
Figure 2 Transcriptional regulation of MHC class I genes. The transcription factors NF-κB, IRF1, and IRF2, and the NLRC5 enhanceosome bind to promoter and enhancer elements in the 5' upstream sequences of MHC I APM genes and drive their transcription. This process is regulated by epigenetic modifications. Methylation of histone (H3K27me3) by histone methyltransferases (HMTs) and DNA methylation repress transcription. Histone acetyltransferases (HATs) acetylate histones, which can open the chromatin for transcription. Histone deacetylases (HDACs) can remove histone acetylation marks and silence transcription.
Figure 2 Transcriptional regulation of MHC class I genes. The transcription factors NF-κB, IRF1, and IRF2, and the NLRC5 enhanceosome bind to promoter and enhancer elements in the 5' upstream sequences of MHC I APM genes and drive their transcription. This process is regulated by epigenetic modifications. Methylation of histone (H3K27me3) by histone methyltransferases (HMTs) and DNA methylation repress transcription. Histone acetyltransferases (HATs) acetylate histones, which can open the chromatin for transcription. Histone deacetylases (HDACs) can remove histone acetylation marks and silence transcription.CC BY · PubMed Central
Figure 3 Interferon signaling stimulates the transcription of MHC class I genes. Binding of Interferon to its receptor stimulates phosphorylation of the Janus kinases, JAK1 and JAK2, which in turn phosphorylate STAT1. Phosphorylated STAT1 translocates into the nucleus where it binds to promoter elements of NLRC5 and IRF1 and drives their transcription. NLRC5 and IRF1 then stimulate MHC I gene transcription as described in Figure 2.
Figure 3 Interferon signaling stimulates the transcription of MHC class I genes. Binding of Interferon to its receptor stimulates phosphorylation of the Janus kinases, JAK1 and JAK2, which in turn phosphorylate STAT1. Phosphorylated STAT1 translocates into the nucleus where it binds to promoter elements of NLRC5 and IRF1 and drives their transcription. NLRC5 and IRF1 then stimulate MHC I gene transcription as described in Figure 2.CC BY · PubMed Central
Figure 4 HLA and β2M are frequently downregulated in many different cancers. This graph illustrates the findings from a number of studies that have measured MHC I expression in various cancers by immunohistochemistry. Cancers are annotated by their TCGA abbreviations (see abbreviation list). Each dot represents the percent of cases with loss of MHC I expression in an individual study. The mean % reductions and standard deviations for all of the studies combined are shown by the black bars. The data to the right of the graph shows the number of studies and number of patients samples used to quantify the MHC class I. The studies that were included are shown in the references; this is not an exhaustive list of all such analyses. BLCA, Bladder urothelial carcinoma; BRCA, Breast invasive carcinoma; CESC, Cervical squamous cell carcinoma and endocervical adenocarcinoma; COAD, Colon adenocarcinoma; ESCA, Esophageal carcinoma; GBM, Glioblastoma multiforme; HNSC, Head and neck squamous cell carcinoma; KIRC, Kidney renal clear cell carcinoma; LSCC, Lung squamous cell carcinoma; HPSCC, Hypopharyngeal squamous cell carcinoma; LUSC, Lung squamous cell carcinoma; OV, Ovarian serous cystadenocarcinoma; PAAD, Pancreatic adenocarcinoma; PRAD, Prostate adenocarcinoma; SARC, Sarcoma; SKCM, Skin cutaneous melanoma; UVM, Uveal melanoma; THCA, Thyroid carcinoma; IFN, Interferon; LIHC, Liver hepatocellular carcinoma; NSCLC, Nonsmall cell lung carcinoma.
Figure 4 HLA and β2M are frequently downregulated in many different cancers. This graph illustrates the findings from a number of studies that have measured MHC I expression in various cancers by immunohistochemistry. Cancers are annotated by their TCGA abbreviations (see abbreviation list). Each dot represents the percent of cases with loss of MHC I expression in an individual study. The mean % reductions and standard deviations for all of the studies combined are shown by the black bars. The data to the right of the graph shows the number of studies and number of patients samples used to quantify the MHC class I. The studies that were included are shown in the references; this is not an exhaustive list of all such analyses. BLCA, Bladder urothelial carcinoma; BRCA, Breast invasive carcinoma; CESC, Cervical squamous cell carcinoma and endocervical adenocarcinoma; COAD, Colon adenocarcinoma; ESCA, Esophageal carcinoma; GBM, Glioblastoma multiforme; HNSC, Head and neck squamous cell carcinoma; KIRC, Kidney renal clear cell carcinoma; LSCC, Lung squamous cell carcinoma; HPSCC, Hypopharyngeal squamous cell carcinoma; LUSC, Lung squamous cell carcinoma; OV, Ovarian serous cystadenocarcinoma; PAAD, Pancreatic adenocarcinoma; PRAD, Prostate adenocarcinoma; SARC, Sarcoma; SKCM, Skin cutaneous melanoma; UVM, Uveal melanoma; THCA, Thyroid carcinoma; IFN, Interferon; LIHC, Liver hepatocellular carcinoma; NSCLC, Nonsmall cell lung carcinoma.CC BY · PubMed Central
Figure 5 Tap1 and Tapasin are downregulated in many cancer types. Similar to Figure 4, except summarizing results from studies quantifying loss of Tap1 (one of the chains of the TAP transporter) and Tapasin, instead of MHC I. There are fewer studies of the expression of these proteins in cancers relative to the studies of MHC I expression in cancers. n/a-data is not available. Cancer abbreviation are as in Figure 4.
Figure 5 Tap1 and Tapasin are downregulated in many cancer types. Similar to Figure 4, except summarizing results from studies quantifying loss of Tap1 (one of the chains of the TAP transporter) and Tapasin, instead of MHC I. There are fewer studies of the expression of these proteins in cancers relative to the studies of MHC I expression in cancers. n/a-data is not available. Cancer abbreviation are as in Figure 4.CC BY · PubMed Central
Figure 6 Frequency of alterations in genomic sequences of MHC class I pathway genes in various cancers. Genomic alterations include any mutation, deletion and/or amplification occurring in either intron or exon regions of the indicated genes. Results were obtained from cBioportal.org (169, 170). analyses of publicly available TCGA data sets for the indicated genes and cancers. APM, Antigen Presentation Machinery. Cancer abbreviation are as in Figure 4.
Figure 6 Frequency of alterations in genomic sequences of MHC class I pathway genes in various cancers. Genomic alterations include any mutation, deletion and/or amplification occurring in either intron or exon regions of the indicated genes. Results were obtained from cBioportal.org (169, 170). analyses of publicly available TCGA data sets for the indicated genes and cancers. APM, Antigen Presentation Machinery. Cancer abbreviation are as in Figure 4.CC BY · PubMed Central
Figure 7 The MHC I antigen presentation pathway is down-regulated by multiple mechanisms in cancers. (i) At the level of DNA, mutation and methylation of nucleotides can reduce expression of APM genes; (ii) Transcription of APM can be reduced by changes in chromatin that impair gene accessibility or through loss of transcription factors. Multiple mechanisms can affect these processes including altered signaling pathways, oncogene activity, and the tumor microenvironment; (iii) At the level of transcription, binding of ncRNA or proteins to the 3′ UTR of APM mRNAs can reduce transcription; (iv) At the level of protein, Staphylococcal nuclease and tudor domain containing 1 (SND1) can bind to MHC I in the ER and trigger endoplasmic reticulum-associated degradation (ERAD). At the cell surface, loss of SPPL3 increases glycosphingolipids (GSL) that then sterically inhibit MHC I and TCR interactions. Reactive nitrogen species can nitrosylate peptide-MHC I complexes in ways that impair TCR interactions.
Figure 7 The MHC I antigen presentation pathway is down-regulated by multiple mechanisms in cancers. (i) At the level of DNA, mutation and methylation of nucleotides can reduce expression of APM genes; (ii) Transcription of APM can be reduced by changes in chromatin that impair gene accessibility or through loss of transcription factors. Multiple mechanisms can affect these processes including altered signaling pathways, oncogene activity, and the tumor microenvironment; (iii) At the level of transcription, binding of ncRNA or proteins to the 3′ UTR of APM mRNAs can reduce transcription; (iv) At the level of protein, Staphylococcal nuclease and tudor domain containing 1 (SND1) can bind to MHC I in the ER and trigger endoplasmic reticulum-associated degradation (ERAD). At the cell surface, loss of SPPL3 increases glycosphingolipids (GSL) that then sterically inhibit MHC I and TCR interactions. Reactive nitrogen species can nitrosylate peptide-MHC I complexes in ways that impair TCR interactions.CC BY · PubMed Central

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  1. Lu, 2000, Decreased HLA-A expression in prostate cancer is associated with normal allele dosage in the majority of cases, J Pathol, 190, 169, 10.1002/(SICI)1096-9896(200002)190:2169::AID-PATH517>3.0.CO;2-# · DOI

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Metadata

Authors
Dhatchinamoorthy, K., Colbert, J. D., & Rock, K. L.
Affiliations
University of Massachusetts Chan Medical School (US)
Corresponding author
Rock, Kenneth L.
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2021-03-09
Volume
12
Pages
636568-636568
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2021.636568
PMC
PMC7986854
OpenAlex
W3134746059
Cited by
1,077
References
429
Citations by year
2026: 209 · 2025: 244 · 2024: 251 · 2023: 202 · 2022: 138 · 2021: 33
FWCI
19.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship@UMassChan (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Cancer Institute (R01CA247624)
  • National Institute of Allergy and Infectious Diseases (R01AI145932)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
tumor immune evasion, MHC class I antigen presentation, MHC class I loss, CD8+ T cells, cancer immunotherapy, immune checkpoint blockade, tumor antigens
MeSH terms
Animals, Humans, Killer Cells, Natural, Mutation, Neoplasms, Transcription, Genetic, Histocompatibility Antigens Class I, Signal Transduction, Gene Expression Regulation, Neoplastic, Lymphocytes, Tumor-Infiltrating, Gene Deletion, Antigen Presentation, Tumor Escape, Tumor Microenvironment

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