Regulation of HLA-DR peptide occupancy by histone deacetylase inhibitors

Cronin, Kevin; Escobar, Hernando Criollo; Szekeres, Károly; Reyes-Vargas, Eduardo; Rockwood, Alan L.; Lloyd, Mark C.; Delgado, Julio; Blanck, George

doi:10.4161/hv.23085

Cited by 14 publications

(27 citation statements)

References 15 publications

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“…Then, the ratios of these so adjusted, anti-CLIP and HLA-DR values were obtained. The HDACIs, Entinostat and Vorinostat, have been shown to alter the CLIP/HLA-DR ratio in the Raji cells, 3 and these alterations are virtually, exactly reproduced in Fig. 1.…”

Section: Resultsmentioning

confidence: 52%

“…Recent work has indicated that HLA-DR epitope resistance correlates with protease expression levels. 3 Thus, to obtain a more global view of the sensitivity of HLA-DR epitopes to proteases, we developed an in silico algorithm, closely related to previously published, publicly available algorithms, for assessing protease sensitivity for a given epitope. Application of the scripted version of the algorithm to the entire set of immune epitope database (IEDB), HLA-DR bound bacterial epitopes indicated that, on average, many of these epitopes are resistant to a variety of proteases (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…3 In particular, cells were stained separately with 4 antibodies, 2 isotype controls, anti-CLIP and anti-HLA-DR. The mean fluorescence values for the isotype controls were subtracted from the anti-CLIP and anti-HLA-DR mean fluorescence values, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…We recently developed a rapid assay for detecting HLA-DR peptidome variations, i.e., by observing changes in the ratio of surface CLIP to HLA-DR. 3 This assay was verified by eluting peptides from Raji B-cells in the presence and absence of the HDACI, Entinostat. Results from this approach indicated that Entinostat upregulated Cathepsin L1, and this in turn led to an increase in the Cathepsin L1 resistant peptides in the HLA-DR peptidome.…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported Entinostat up-regulation of Cathepsin L1 in Raji B-cells and an accompanying replacement of Cathepsin L1 sensitive, human peptides by Cathepsin L1 resistant peptides, 3 which led to the question of how frequently small molecules may be expected to alter the MHC class II peptidome, as represented by HLA-DR bound peptides in immortalized B-cells? Some of the small molecules in this study represent FDA approved drugs, to get a basic appreciation of possible, unexpected peptidome alterations in patients, which in turn could unexpectedly impact their immune responses.…”

Section: Introductionmentioning

confidence: 99%

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HLA-DR peptide occupancy can be regulated with a wide variety of small molecules

Blazekovic

Odukoya

Butler

et al. 2015

Human Vaccines & Immunotherapeutics

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HLA-DR is the most commonly expressed and likely the most medically important human MHC class II, antigen presenting protein. In a normal immune response, HLA-DR binds to antigenic peptide and the HLA-DR/peptide complex binds to a T-cell receptor, thus contributing to T-cell activation and stimulation of an immune response against the antigen. When foreign antigen is not present, HLA-DR binds endogenous peptide which, under normal conditions does not stimulate an immune response. In most cases, the human peptide is CLIP, but a certain percentage of HLA-DR molecules will be present at the cell surface with other human peptides. We have recently shown that cell surface, CLIP/HLA-DR ratios are a measure of peptide heterogeneity, and in particular, changes in CLIP/HLA-DR ratios represent changes in the occupancy of HLA-DR by other, endogenous peptides. For example, treatment of cells with the HDAC inhibitor, Entinostat, leads to an upregulation of Cathepsin L1 and replacement of Cathepsin L1 senstitive peptides with HLA-DR binding, Cathepsin L1 resistant peptides, an alteration that can be at least partially assessed via assessment of CLIP/HLA-DR cell surface ratios. Here we assay for CLIP/HLA-DR ratios following treatment of immortalized B-cells with a variety of common drugs, almost all of which indicate significant changes in the CLIP/HLA-DR ratios. Furthermore, the CLIP/HLA-DR ratio changes parallel the impact of the drug panoply on cell viability, suggesting that alterations in the HLA-DR peptidome are governed by a variety of mechanisms, rather than exclusively dependent on a dedicated peptide loading process. These results raise questions about how FDA approved drugs may affect the immune response, and whether any of these drugs could be useful as vaccine adjuvants?

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Section: Resultsmentioning

confidence: 52%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

HLA-DR peptide occupancy can be regulated with a wide variety of small molecules

Blazekovic

Odukoya

Butler

et al. 2015

Human Vaccines & Immunotherapeutics

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Assessing microenvironment immunogenicity using tumor specimen exomes: Co-detection of TcR-α/β V(D)J recombinations correlates with PD-1 expression

Wei

Samy

et al. 2017

Int. J. Cancer

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T-cell receptor (TcR) recombinations can be recovered from tumor specimen, whole exome sequences (WXS) files. However, it is not yet clear how these recombinations represent lymphocytes or an anti-tumor immune response. Here we report the identification of productive TcR-β recombinations in WXS files representing primary and metastatic melanoma. The recombinations are identifiable in about 20% of the cancer genome atlas melanoma samples. This frequency of detection is lower than the frequency of TcR-α VJ recombinations, consistent with the occurrence of biallelic TcR-α recombinations and possibly consistent with the fact that only one junctional recombination is required for TcR-α whereas two recombinations are required to form a TcR-β gene. Nevertheless, the ratio of productive TcR-β to unproductive TcR-β samples, in comparison to the ratio of productive to unproductive TcR-α or TcR-γ positive-samples, is very high. This result indicates that detection of a productive TcR-β VDJ recombination represents a comparatively high standard for potential antigen binding capacity, when employing a tumor specimen exome file for the assessment. Additionally, PD-1 expression and antigen presentation functions correlated with the co-detection of TcR-α and -β recombinations (e.g., p < 0.0004), suggesting that co-detection of TcR-α and -β recombinations represents an anti-melanoma response that has been blunted by the advent of PD-1 expression. We further show that the algorithm for detecting the TcR-β VDJ recombinations is applicable to exome files generated from mouse tissue, thus providing for opportunities to develop empirical paradigms for interpreting the identification of TcR V(D)J recombinations in tissue resident lymphocytes.

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Cytoskeleton and ECM tumor mutant peptides: Increased protease sensitivities and potential consequences for the HLA class I mutant epitope reservoir

Callahan¹,

Patel²,

Fawcett

et al. 2017

Intl Journal of Cancer

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Cytoskeleton and extracellular matrix-related proteins (CECMPs) represent the most common class of cancer mutants, owing to the large size of their coding regions and the randomness of mutagenesis. We used a bioinformatics approach to assess the impact of amino acid (AA) substitutions on the sensitivity of CECMPs to proteases relevant to melanoma and on the binding affinities for HLA class I. CECMP peptides with AA substitutions overwhelmingly reflect increased sensitivity to proteases implicated in melanoma development (MME, CTSS, MMP2, CTSD, CTSL) in comparison to the wild-type peptide sequences. Furthermore, peptides with AA substitutions representing increased peptide protease sensitivity also represented relatively high binding affinities for HLA class I allelic variants. These analyses raise the question of whether increased protease sensitivity, of mutant cancer peptides represents a significant increase in the availability of cancer mutant, HLA class I epitopes and a hitherto unappreciated aspect of cancer cell immunogenicity, particularly in the case of melanoma?

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Regulation of HLA-DR peptide occupancy by histone deacetylase inhibitors

Cited by 14 publications

References 15 publications

HLA-DR peptide occupancy can be regulated with a wide variety of small molecules

HLA-DR peptide occupancy can be regulated with a wide variety of small molecules

Assessing microenvironment immunogenicity using tumor specimen exomes: Co-detection of TcR-α/β V(D)J recombinations correlates with PD-1 expression

Cytoskeleton and ECM tumor mutant peptides: Increased protease sensitivities and potential consequences for the HLA class I mutant epitope reservoir

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