HLA antigen changes in malignant cells: epigenetic mechanisms and biologic significance

Campoli, Michael; Ferrone, Soldano

doi:10.1038/onc.2008.273

Cited by 364 publications

(321 citation statements)

References 134 publications

(240 reference statements)

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“…Furthermore, this bottleneck of the antigen processing pathway is frequently targeted by viruses, especially from the herpes group, which successfully evade complete eradication by CTL immunity [15,16]. Moreover, loss of TAP expression is often found in cancers and results in resistance to CTL attack [17][18][19]. All these findings together convincingly demonstrate that the conventional proteasome-TAP pathway plays a dominant role in the surface display of peptide/MHC-I.…”

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confidence: 84%

“…These peptide sequences, called TEIPP (T-cell epitopes associated with impaired peptide processing), are not presented by normal cells and we can speculate, based on the results of the present study, that one mechanism governing the absence from normal cells is related to the low expression level of the cognate proteins. In a parallel study, a proteasome-and TAPindependent tumor antigen from the signal sequence of the preprocalcitonin protein (ppCT [16][17][18][19][20][21][22][23][24][25] ) was found to represent a human TEIPP, in that this HLA-A2 presented peptide was selectively presented by tumor cells with TAP deficiency [54]. This peptide is liberated in the ER lumen by sequential cleavage with SP and SPP [55] and is a clear example of the alternative TAP-independent peptide repertoire.…”

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confidence: 99%

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Peptide transporter TAP mediates between competing antigen sources generating distinct surface MHC class I peptide repertoires

et al. 2011

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We recently described a category of TAP-independent peptide-epitopes that are selectively presented by cells with processing defects in the classical MHC class I (MHC-I) pathway. Here, we studied the ER-resident ceramide synthase Trh4 as a prototypic example of these neo-antigens and found that moderate inhibition of TAP permits cell surface presentation of the Trh4 peptide. The absence of this peptide from WT cells was not related to the binding or stability of the Trh4/D b complexes, or to the availability of MHC-I heavy chains, but rather to the limited expression of the antigen. Strongly elevated antigen levels were needed to reach comparable peptide display on WT as on TAP-deficient cells. Our data suggest that the normal influx of TAP-transported peptides in the ER during routine processing creates an efficient barrier for peptides from alternative processing routes. Impairment of TAP function, as commonly found in cancers and virus-infected cells, lowers this resistance allowing for MHC-I presentation of other peptide sources.Key words: Antigen processing . Cytotoxic T lymphocytes . Transporter associated with peptide processing Supporting Information available online IntroductionCytotoxic T lymphocytes (CTLs) are key effector cells of the adaptive immune system and circulate throughout the body in search of their cognate peptides that are presented by MHC class I (MHC-I) molecules. T-cell receptors determine the antigen specificity of CTLs and engagement with peptide/MHC-I complexes leads to their activation and elimination of target cells. Therefore, the process of MHC-I antigen processing and presentation, which operates in all nucleated cells of our body, is crucial for CTL immune surveillance [1][2][3]. The highly complex repertoire of MHC-I presented peptides reflects the total proteome of cells and derives from the physiological turnover of proteins, a process that is largely operated by the multicatalytic enzyme proteasome [4,5]. In addition to the proteasome, other proteolytic enzymes in the cytosol have been implicated in the liberation of peptides for MHC-I presentation, some of which can compensate for the lack of proteasome activity [1,6,7]. For instance, tripeptidyl peptidase II (TPPII), insulin-degrading enzyme (IDE), thimet oligopeptidase (TOP) and nardilysin have been implicated in the generation of some CTL epitopes [8][9][10]. However, the relative contributions of these novel peptidases and Ã These authors contributed equally to this work 3114their cooperation with the proteasome have not been fully characterized.The intermediate peptide products are rescued from total breakdown by these cytosolic proteases through translocation into the ER. Subsequently, peptides are trimmed and loaded into the grooves of MHC-I molecules, a dynamic process that is mediated by the peptide loading complex (PLC) consisting of MHC-I, b2m, ERp57, TAP, tapasin and chaperones [11][12][13]. The TAP peptide transport is operated by the heterodimer pump TAP1/TAP2, members of the ABC transporter family. The imp...

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Peptide transporter TAP mediates between competing antigen sources generating distinct surface MHC class I peptide repertoires

et al. 2011

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“…29 Tumors may escape from immunosurveillance through the mutation of a single, immunodominant T-cell epitope or through the down-regulation of a specific human leukocyte antigen (HLA) allele. 30,31 By including multiple immunogenic epitopes, long-peptide vaccines may interact with many more HLA class I and class II alleles than short peptides. If CTLs could be raised against additional epitopes, creating a broad Tcell response against many epitopes, then such tumor escape variants would have less opportunity to establish metastases.…”

Section: Therapeutic Vaccines Combined With Chemotherapymentioning

confidence: 99%

A new era in anticancer peptide vaccines

Perez

Hofe

Kallinteris

et al. 2010

Cancer

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The use of synthetic peptides as vaccines aimed at the induction of therapeutic CD8-positive T-cell responses against tumor cells initially experienced great enthusiasm, mostly because of advances in vaccine technology, including design, synthesis, and delivery. However, despite impressive results in animal models, the application of such vaccines in humans has met with only limited success. The therapeutic activity of vaccine-stimulated, tumor-specific, CD8-positive T cells can be hampered through the physical burden of the tumor, tolerance mechanisms, and local factors within the tumor microenvironment. Recently, accumulating evidence has suggested that combining a peptide-based therapeutic vaccination with conventional chemotherapy can uncover the full potential of the antitumor immune response, increasing the success of immunotherapy. In addition, therapeutic vaccination in the preventive setting has been extremely effective in eliciting antitumor responses in preclinical tumor models and has demonstrated good promise clinically in patients with minimal residual disease. The rationale behind preventive vaccination is that patients with minimal tumor burden still have a fully competent immune system capable of developing robust antitumor responses. Finally, therapeutic CD8-positive T-cell peptide vaccines have been improved by coimmunization with T-helper epitopes expressed on long peptides.

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“…It has been demonstrated that cancer cells use multiple strategies of immune evasion, including increased resistance to cytotoxic T-cell killing, induction of anergy in activated T cells, elimination of effector T cells, recruitment of regulatory immune cell subsets, and reduced recognition of tumor-associated antigens by effector T cells (2). Impaired MHC class I-mediated antigen presentation is a major immune evasion mechanism in cancer (3,4), with MHC class I loss reported in cervical cancer (92%) (5), penile cancer (80%) (6), breast cancer (71%) (7), nonsmall cell lung cancer (64%) (8), and esophageal squamous cell carcinoma (67%) (9), among others. Although a number of mechanisms have been described for HLA loss, including the loss of heterozygosity, HLA gene methylation, nonsense/ missense mutations, and loss of TAP1/2 or β2-microglobulin (B2M), the dominant underlying molecular mechanism seems to reside at the transcriptional level (10).…”

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NLRC5/MHC class I transactivator is a target for immune evasion in cancer

Yoshihama

Roszik

Downs

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

226

242

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Cancer cells develop under immune surveillance, thus necessitating immune escape for successful growth. Loss of MHC class I expression provides a key immune evasion strategy in many cancers, although the molecular mechanisms remain elusive. MHC class I transactivator (CITA), known as "NLRC5" [NOD-like receptor (NLR) family, caspase recruitment (CARD) domain containing 5], has recently been identified as a critical transcriptional coactivator of MHC class I gene expression. Here we show that the MHC class I transactivation pathway mediated by CITA/NLRC5 constitutes a target for cancer immune evasion. In all the 21 tumor types we examined, NLRC5 expression was highly correlated with the expression of MHC class I, with cytotoxic T-cell markers, and with genes in the MHC class I antigen-presentation pathway, including LMP2/LMP7, TAP1, and β2-microglobulin. Epigenetic and genetic alterations in cancers, including promoter methylation, copy number loss, and somatic mutations, were most prevalent in NLRC5 among all MHC class I-related genes and were associated with the impaired expression of components of the MHC class I pathway. Strikingly, NLRC5 expression was significantly associated with the activation of CD8 + cytotoxic T cells and patient survival in multiple cancer types. Thus, NLRC5 constitutes a novel prognostic biomarker and potential therapeutic target of cancers.MHC class I | CITA | cancer | immune evasion | NLRC5

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HLA antigen changes in malignant cells: epigenetic mechanisms and biologic significance

Cited by 364 publications

References 134 publications

Peptide transporter TAP mediates between competing antigen sources generating distinct surface MHC class I peptide repertoires

Peptide transporter TAP mediates between competing antigen sources generating distinct surface MHC class I peptide repertoires

A new era in anticancer peptide vaccines

NLRC5/MHC class I transactivator is a target for immune evasion in cancer

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