Restoration of the Expression of Transporters Associated with Antigen Processing in Lung Carcinoma Increases Tumor-Specific Immune Responses and Survival

Lou, Yuanmei; Vitalis, Timothy Z.; Basha, Genc; Cai, Bing; Chen, Susan S.; Choi, Kyung Bok; Jeffries, Andrew P.; Elliott, W. Mark; Atkins, Derek; Seliger, Barbara; Jefferies, Wilfred A.

doi:10.1158/0008-5472.can-04-3977

Cited by 77 publications

(54 citation statements)

References 27 publications

(28 reference statements)

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“…TAP downregulation has also been observed in several SCLC and NSCLC specimens by immunohistochemical analysis (42)(43)(44). This suggested that human cancers, including lung cancers, represent poor targets for MHC-I-restricted CTLs and thus correspond to poor candidates for tumor-associated Ag-based immunotherapy (42)(43)(44)(45)(46). However, we show in this study that tumor Ag can be presented on cancer cells after degradation by at least two parallel mechanisms, which together contribute to the diversity of antigenic peptides displayed at the surface of malignant cells.…”

Section: Discussionmentioning

confidence: 99%

Different Expression Levels of the TAP Peptide Transporter Lead to Recognition of Different Antigenic Peptides by Tumor-Specific CTL

Durgeau

Hage

Vergnon

et al. 2011

The Journal of Immunology

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Decreased antigenicity of cancer cells is a major problem in tumor immunology. This is often acquired by an expression defect in the TAP. However, it has been reported that certain murine Ags appear on the target cell surface upon impairment of TAP expression. In this study, we identified a human CTL epitope belonging to this Ag category. This epitope is derived from preprocalcitonin (ppCT) signal peptide and is generated within the endoplasmic reticulum by signal peptidase and signal peptide peptidase. Lung cancer cells bearing this antigenic peptide displayed low levels of TAP, but restoration of their expression by IFN-γ treatment or TAP1 and TAP2 gene transfer abrogated ppCT Ag presentation. In contrast, TAP upregulation in the same tumor cells increased their recognition by proteasome/TAP-dependent peptide-specific CTLs. Thus, to our knowledge, ppCT16–25 is the first human tumor epitope whose surface expression requires loss or downregulation of TAP. Lung tumors frequently display low levels of TAP molecules and might thus be ignored by the immune system. Our results suggest that emerging signal peptidase-generated peptides represent alternative T cell targets, which permit CTLs to destroy TAP-impaired tumors and thus overcome tumor escape from CD8+ T cell immunity.

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Section: Discussionmentioning

confidence: 99%

Different Expression Levels of the TAP Peptide Transporter Lead to Recognition of Different Antigenic Peptides by Tumor-Specific CTL

Durgeau

Hage

Vergnon

et al. 2011

The Journal of Immunology

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“…8,9 Loss of tapasin expression is a frequent event that has been reported in a wide variety of human cancers, including malignant melanoma, head and neck squamous cell carcinoma (HNSCC), renal cell carcinoma, colorectal carcinoma, glioblastoma, lung carcinoma, and neuroblastoma. [10][11][12][13][14][15][16][17][18] Notably, tapasin expression associated with intratumoral T-cell infiltration has been reported as a prognostic marker of patient survival in ovarian carcinoma, HNSCC, glioblastoma, and colorectal carcinoma. 12,13,[19][20][21] It is also reported that loss of tapasin is more frequent among the other antigen-processing machinery (APM) components, strongly suggesting its central role in escape from CTL immune surveillance to tumors.…”

Section: Introductionmentioning

confidence: 99%

Loss of tapasin in human lung and colon cancer cells and escape from tumor-associated antigen-specific CTL recognition

et al. 2017

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Cytotoxic T-lymphocytes (CTLs) lyse target cells after recognizing the complexes of peptides and MHC class I molecules (pMHC I) on cell surfaces. Tapasin is an essential component of the peptide-loading complex (PLC) and its absence influences the surface repertoire of MHC class I peptides. In the present study, we assessed tapasin expression in 85 primary tumor lesions of non-small cell lung cancer (NSCLC) patients, demonstrating that tapasin expression positively correlated with patient survival. CD8C T-cell infiltration of tumor lesions was synergistically observed with tapasin expression and correlated positively with survival. To establish a direct link between loss of tapasin and CTL recognition in human cancer models, we targeted the tapasin gene by CRISPR/Cas9 system and generated tapasin-deficient variants of human lung as well as colon cancer cells. We induced the CTLs recognizing endogenous tumor-associated antigens (TAA), survivin or cep55, and they responded to each tapasin-proficient wild type. In contrast, both CTL lines ignored the tapasin-deficient variants despite their antigen expression. Moreover, the adoptive transfer of the cep55-specific CTL line failed to prevent tumor growth in mice bearing the tapasindeficient variant. Loss of tapasin most likely limited antigen processing of TAAs and led to escape from TAA-specific CTL recognition. Tapasin expression is thus a key for CTL surveillance against human cancers.

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“…Treatment with IFN-γ and TNF-α [12,32] or transfection of specific genes including TAP1 and TAP2 [36] can restore MHC class I expression in certain tumor cells treated in vitro with these agents. In addition, restoration of TAP activity by transfection of tumor cells enhances class I mediated antigen presentation and induces susceptibility to CTL killing, both in vitro and in vivo [1,23]. In contrast, IFN-γ and TNF-α treatment failed to elicit class I expression in some class I deficient tumors which are associated with a defective β 2 m gene [5] or DNA hypermethylation [40].…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase inhibitors induce TAP, LMP, Tapasin genes and MHC class I antigen presentation by melanoma cells

Khan

Gregorie

Tomasi

2007

Cancer Immunol Immunother

176

124

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Histone deacetylase inhibitors (HDACi), including trichostatin A (TSA) and valproic acid, can alter the acetylation of histones in chromatin and enhance gene transcription. Previously we demonstrated that HDACi-treated tumor cells are capable of presenting antigen via the MHC class II pathway. In this study, we show that treatment with HDACi enhances the expression of molecules (TAP1, TAP2, LMP2, LMP7, Tapasin and MHC class I) involved in antigen processing and presentation via the MHC class I pathway in melanoma cells. HDACi treatment of B16F10 cells also enhanced cell surface expression of class I and costimulatory molecules CD40 and CD86. Enhanced transcription of these genes is associated with a significant increase in direct presentation of whole protein antigen and MHC class I-restricted peptides by TSA-treated B16F10 cells. Our data indicate that epigenetic modification can convert a tumor cell to an antigen presenting cell capable of activating IFN-γ secreting T cells via the class I pathway. These findings suggest that the abnormalities, observed in some tumors in the expression of MHC class I antigen processing and presentation molecules, may result from epigenetic repression.

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Restoration of the Expression of Transporters Associated with Antigen Processing in Lung Carcinoma Increases Tumor-Specific Immune Responses and Survival

Cited by 77 publications

References 27 publications

Different Expression Levels of the TAP Peptide Transporter Lead to Recognition of Different Antigenic Peptides by Tumor-Specific CTL

Different Expression Levels of the TAP Peptide Transporter Lead to Recognition of Different Antigenic Peptides by Tumor-Specific CTL

Loss of tapasin in human lung and colon cancer cells and escape from tumor-associated antigen-specific CTL recognition

Histone deacetylase inhibitors induce TAP, LMP, Tapasin genes and MHC class I antigen presentation by melanoma cells

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