Tumor-targeted silencing of the peptide transporter TAP induces potent antitumor immunity

Garrido, Greta; Schrand, Brett; Rabasa, Ailem; Levay, Agata; D’Eramo, Francesca; Berezhnoy, Alexey; Modi, Shrey; Gefen, Tal; Marijt, Koen A.; Doorduijn, Elien M.; Dudeja, Vikas; Hall, Thorbald van; Gilboa, Eli

doi:10.1038/s41467-019-11728-2

Cited by 53 publications

(46 citation statements)

References 56 publications

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“…As tumor deaths depend on the transportation of proteins with the help of TAP1, it becomes a prospective biomarker for cancer. Though low TAP1 expression is related with tumor development and alteration of TAP1 may lead to evasion of cytotoxic T-cell killing of some cancer cells [30], but studies are downregulating TAP1 as a way to promote neoantigens as tumor immunity [31]. The consideration of microenvironment for tumor seems essential regarding the expression of a gene as TAP1 as its regulation may be determined by proteins like STAT1 and IRF1.…”

Section: Discussionmentioning

confidence: 99%

Transporter Associated with Antigen Processing 1 (TAP1) as a Potential Biomarker for Breast, Lung, Liver and Ovarian Cancer using Health Informatics

Tabassum¹,

Samdani²,

Dhali³

et al. 2020

Preprint

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Transporter associated with antigen processing 1 (TAP1) gene codes for a transporter protein, which is responsible for tumor antigen presentation in the MHC I or HLA complex. A defect in the gene results in an inadequate tumor tracking. TAP1 may also influence multi drug resistance, which is an extreme threat in providing treatment by drugs which are chemotherapeutic. The gene of TAP1 was analyzed bioinformatically. It gave us prognostic data as a confirmation of whether it should be used as a biomarker. The expression level and pattern analysis were conducted using ONCOMINE, GENT2 and GEPIA2 online platforms. Samples with different clinical outcomes were investigated for expression and promoter methylation analysis was done in cancer vs normal tissues using UALCAN. The copy number alteration and mutation frequency and expression in different cancer studies were analyzed using cBioPortal. The PrognoScan and KM plotter survival analysis of significant data (p-value<0.05) was representing graphically. Pathway and Gene ontology analysis of gene correlated to TAP1 gene was presented using bar charts. After arranging the data in a single panel and correlating expression to prognosis, understanding mutational and alterations and comparing pathways, TAP1 may be a potential novel target to evade a threat against chemotherapy and the study gives new aspects to consider for immunotherapy in human breast, lung, liver and ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Transporter Associated with Antigen Processing 1 (TAP1) as a Potential Biomarker for Breast, Lung, Liver and Ovarian Cancer using Health Informatics

Tabassum¹,

Samdani²,

Dhali³

et al. 2020

Preprint

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show abstract

“…Interestingly, tumor cells with such antigen processing defects still express MHC-I molecules, which then present T cell epitopes associated with impaired peptide processing (TEIPP) [82][83][84]. Priming TEIPP-specific T cells with vaccines to overcome acquired immune resistance has been proposed as a treatment strategy for tumors with impaired TAP expression, and this approach has been proven effective in inhibiting the outgrowth of immune-escaped tumors in mice [85,86]. Unexpectedly, the expression of MHC-II molecules was also detected on tumor cells and shown to correlate with T cell infiltration and the therapeutic response to CPI, indicating the presence of alternative antigen presentation pathways [87,88].…”

Section: Tumor Cell Intrinsic Primary Resistance Mechanismsmentioning

confidence: 99%

Future Challenges in Cancer Resistance to Immunotherapy

Elsas

Hall

Burg

2020

Cancers

Self Cite

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Cancer immunotherapies, including checkpoint inhibitors, adoptive T cell transfer and therapeutic cancer vaccines, have shown promising response rates in clinical trials. Unfortunately, there is an increasing number of patients in which initially regressing tumors start to regrow due to an immunotherapy-driven acquired resistance. Studies on the underlying mechanisms reveal that these can be similar to well-known tumor intrinsic and extrinsic primary resistance factors that precluded the majority of patients from responding to immunotherapy in the first place. Here, we discuss primary and secondary immune resistance and point at strategies to identify potential new mechanisms of immune evasion. Ultimately, this may lead to improved immunotherapy strategies with improved clinical outcomes.

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“…T cells against an epitope derived from the leader sequence of LDL receptor-associated protein 1 (LRPAP1) are shown to recognize TAP-deficient tumor cells of different histological origins, but not healthy cells 71 . Based on these findings, recent studies focused on the evaluation of a therapeutic model that involved the use of targeted knockdown of TAP in tumor cells to enhance the efficacy of conventionally used checkpoint inhibitors and to test the potential of TEIPP-based peptide vaccines in cancer therapy 72 , 73 . The success of these strategies in the clinic, though promising, is bound to be affected by several factors, including the HLA-I genotype of the patients, identity of specific antigens being tested, and the type of cancer.…”

Section: Some Hla-i Variants Can Acquire Peptides Via Tap- and Tapasimentioning

confidence: 99%

Variations in MHC class I antigen presentation and immunopeptidome selection pathways

2020

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Major histocompatibility class I (MHC-I) proteins mediate immunosurveillance against pathogens and cancers by presenting antigenic or mutated peptides to antigen receptors of CD8+ T cells and by engaging receptors of natural killer (NK) cells. In humans, MHC-I molecules are highly polymorphic. MHC-I variations permit the display of thousands of distinct peptides at the cell surface. Recent mass spectrometric studies have revealed unique and shared characteristics of the peptidomes of individual MHC-I variants. The cell surface expression of MHC-I–peptide complexes requires the functions of many intracellular assembly factors, including the transporter associated with antigen presentation (TAP), tapasin, calreticulin, ERp57, TAP-binding protein related (TAPBPR), endoplasmic reticulum aminopeptidases (ERAPs), and the proteasomes. Recent studies provide important insights into the structural features of these factors that govern MHC-I assembly as well as the mechanisms underlying peptide exchange. Conformational sensing of MHC-I molecules mediates the quality control of intracellular MHC-I assembly and contributes to immune recognition by CD8 at the cell surface. Recent studies also show that several MHC-I variants can follow unconventional assembly routes to the cell surface, conferring selective immune advantages that can be exploited for immunotherapy.

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Tumor-targeted silencing of the peptide transporter TAP induces potent antitumor immunity

Cited by 53 publications

References 56 publications

Transporter Associated with Antigen Processing 1 (TAP1) as a Potential Biomarker for Breast, Lung, Liver and Ovarian Cancer using Health Informatics

Transporter Associated with Antigen Processing 1 (TAP1) as a Potential Biomarker for Breast, Lung, Liver and Ovarian Cancer using Health Informatics

Future Challenges in Cancer Resistance to Immunotherapy

Variations in MHC class I antigen presentation and immunopeptidome selection pathways

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