MHC Class I Regulation: The Origin Perspective

Sznarkowska, Alicja; Mikac, Sara; Pilch, Magdalena

doi:10.3390/cancers12051155

Cited by 14 publications

(8 citation statements)

References 178 publications

(209 reference statements)

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“…To explore the regulatory mechanisms of B2M expression, we searched for TFs that are positively or negatively correlated with B2M expression in LUAD tumours (Figure 5a). IRF1 and STAT1 are two TFs known to mediate IFN‐γ‐induced B2M expression [44‐46]. STAT5A was also positively associated with B2M expression in LUAD tumours, and analyses of several datasets consistently showed that LUAD tissues expressed lower levels of STAT5A than normal tissues (Figure F).…”

Section: Resultsmentioning

confidence: 93%

B2M gene expression shapes the immune landscape of lung adenocarcinoma and determines the response to immunotherapy

et al. 2021

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Loss of the B2M gene is associated with tumour immune escape and resistance to immunotherapy. However, genetic alterations of the B2M gene are rare. We performed an integrative analysis of the mutational and transcriptional profiles of large cohorts of non‐small‐cell lung cancer (NSCLC) patients and found that epigenetic downregulation of B2M is common. B2M‐low tumours exhibit a suppressive immune microenvironment characterized by reduced infiltration of immune cells of various lineages; in B2M‐high tumours, more T and natural killer cells are present, but their activities are constrained by immune checkpoint molecules, indicating the diverse mechanisms of immune evasion. High levels of B2M mRNA, but not PD‐L1, are correlated with an enhanced response to PD‐1‐based immunotherapy, suggesting its value for immunotherapy response prediction in solid tumours. Notably, a high tumour mutation burden (TMB) is associated with low B2M expression, which may explain the poor predictive value of the TMB in some situations. In syngeneic mouse models, genetic ablation of B2M in tumour cells causes resistance to PD‐1‐based immunotherapy, and B2M knockdown also diminishes the therapeutic efficacy. Moreover, forced expression of B2M in tumour models improves the response to immunotherapy, suggesting that B2M levels have significant impacts on treatment outcomes. Finally, we provide insight into the roles of transcription factors and KRAS mutations in B2M expression and the anticancer immune response. In conclusion, genetic and epigenetic regulation of B2M fundamentally shapes the NSCLC immune microenvironment and may determine the response to checkpoint blockade‐based immunotherapy.

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Section: Resultsmentioning

confidence: 93%

B2M gene expression shapes the immune landscape of lung adenocarcinoma and determines the response to immunotherapy

et al. 2021

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“…In this regard, the MHC haplotype comprising a cluster of multilocus, monocistronic expression units is analogous to the polycistronic bacterial operon, which is a functional unit of DNA containing a cluster of genes under the control of a single promoter (Lee and Sonnhammer, 2003 ; Blumenthal, 2004 ). However, the MHC haplotype structures are far more complex with their regulatory network of cis-acting multilocus expression units known as haplotype-specific expression quantitative trait loci (eQTL) (Lamontagne et al, 2016 ; Lam et al, 2017 ) that are largely controlled by an array of virus-derived REs and DNA transposons, both as binding sites for transcription factors and as sources of regulatory non-coding RNAs (Kulski, 2019 ; Sznarkowska et al, 2020 ). Random mutations, methylations and recombinations can generate considerable haplotype diversity that is part of the MHC immune system's response to highly prevalent infectious (Gao et al, 2019 ; Sanchez-Mazas, 2020 ) and chemical agents, including those responsible for drug hypersensitivities (Alfirevic and Pirmohamed, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

SNP-Density Crossover Maps of Polymorphic Transposable Elements and HLA Genes Within MHC Class I Haplotype Blocks and Junction

2021

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The genomic region (~4 Mb) of the human major histocompatibility complex (MHC) on chromosome 6p21 is a prime model for the study and understanding of conserved polymorphic sequences (CPSs) and structural diversity of ancestral haplotypes (AHs)/conserved extended haplotypes (CEHs). The aim of this study was to use a set of 95 MHC genomic sequences downloaded from a publicly available BioProject database at NCBI to identify and characterise polymorphic human leukocyte antigen (HLA) class I genes and pseudogenes, MICA and MICB, and retroelement indels as haplotypic lineage markers, and single-nucleotide polymorphism (SNP) crossover loci in DNA sequence alignments of different haplotypes across the Olfactory Receptor (OR) gene region (~1.2 Mb) and the MHC class I region (~1.8 Mb) from the GPX5 to the MICB gene. Our comparative sequence analyses confirmed the identity of 12 haplotypic retroelement markers and revealed that they partitioned the HLA-A/B/C haplotypes into distinct evolutionary lineages. Crossovers between SNP-poor and SNP-rich regions defined the sequence range of haplotype blocks, and many of these crossover junctions occurred within particular transposable elements, lncRNA, OR12D2, MUC21, MUC22, PSORS1A3, HLA-C, HLA-B, and MICA. In a comparison of more than 250 paired sequence alignments, at least 38 SNP-density crossover sites were mapped across various regions from GPX5 to MICB. In a homology comparison of 16 different haplotypes, seven CEH/AH (7.1, 8.1, 18.2, 51.x, 57.1, 62.x, and 62.1) had no detectable SNP-density crossover junctions and were SNP poor across the entire ~2.8 Mb of sequence alignments. Of the analyses between different recombinant haplotypes, more than half of them had SNP crossovers within 10 kb of LTR16B/ERV3-16A3_I, MLT1, Charlie, and/or THE1 sequences and were in close vicinity to structurally polymorphic Alu and SVA insertion sites. These studies demonstrate that (1) SNP-density crossovers are associated with putative ancestral recombination sites that are widely spread across the MHC class I genomic region from at least the telomeric OR12D2 gene to the centromeric MICB gene and (2) the genomic sequences of MHC homozygous cell lines are useful for analysing haplotype blocks, ancestral haplotypic landscapes and markers, CPSs, and SNP-density crossover junctions.

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“…Although HLA class I molecules are known to be expressed at the basal state in almost all nucleated cells, this expression can be induced or repressed through various mechanisms including interferon signaling and transcription factors of nuclear factor-κB (NF-κB) and NLRC5, etc. by the cell itself or its surrounding immune cells 25 . Thus, we suppose that increased HLA class I expression in IBC compared to DCIS in HR-negative tumors would be related to the degree of immune cell infiltration and induction of HLA class I by the immune cells as IBC generally shows higher immune cell infiltration than DCIS, which is a finding more prominent in HR-negative tumors.…”

Section: Discussionmentioning

confidence: 99%

Expression of HLA class I is associated with immune cell infiltration and patient outcome in breast cancer

Han

Kim

Chung³

et al. 2022

Sci Rep

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Downregulation of human leukocyte antigen (HLA) class I is one mechanism of escaping anti-tumor immunity by tumor cells. This study was conducted to compare HLA class I expression in ductal carcinoma in situ (DCIS) and invasive breast carcinoma (IBC) and to evaluate its association with immune cell infiltration of the tumors and clinical outcome of the patients. A total of 830 cases comprising 288 DCIS and 542 IBC were included in this study. Immunohistochemistry for HLA class I expression was performed using HLA-ABC in tissue microarrays and was analyzed in relation to clinicopathologic characteristics of tumors and infiltration of CD4+, CD8+, and FOXP3+ tumor-infiltrating lymphocyte (TIL) subsets and PD-L1+ immune cells. As a whole, there was no difference in HLA class I expression between DCIS and IBC when dichotomized into high or low expression. However, in the HR-negative group, a high level of HLA class I expression was more frequent in IBC than DCIS. On the contrary, in the HR-positive group, a complete loss of HLA class I expression was more frequently observed in IBC than DCIS. High HLA class I expression level was generally associated with aggressive clinicopathologic features of IBC and was associated with high CD4+, CD8+, and FOXP3+ TIL and PD-L1+ immune cell infiltration in both DCIS and IBC. In survival analyses, HLA class I expression was not associated with clinical outcome in DCIS and IBC as a whole; however, low HLA class I expression was associated with poor clinical outcome in HR-negative IBC, especially in triple-negative subtype. In conclusion, this study showed that HLA class I expression increased in association with increased immune cell infiltration during in situ to invasive transition of HR-negative breast cancer, and HLA class I down-regulation had a prognostic value in HR-negative breast cancer.

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MHC Class I Regulation: The Origin Perspective

Cited by 14 publications

References 178 publications

B2M gene expression shapes the immune landscape of lung adenocarcinoma and determines the response to immunotherapy

B2M gene expression shapes the immune landscape of lung adenocarcinoma and determines the response to immunotherapy

SNP-Density Crossover Maps of Polymorphic Transposable Elements and HLA Genes Within MHC Class I Haplotype Blocks and Junction

Expression of HLA class I is associated with immune cell infiltration and patient outcome in breast cancer

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