Combining the Antigen Processing Components TAP and Tapasin Elicits Enhanced Tumor-Free Survival

Lou, Yuanmei; Basha, Genc; Seipp, Robyn P.; Cai, Bing; Chen, Susan S.; Moise, Alexander R.; Jeffries, Andrew P.; Gopaul, Ray S.; Vitalis, Timothy Z.; Jefferies, Wilfred A.

doi:10.1158/1078-0432.ccr-07-1066

Cited by 39 publications

(30 citation statements)

References 36 publications

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“…[19][20][21]24 A former study has demonstrated that restoring tapasin gene expression in a mouse tumor model using viral vector transduction improved survival of model mice bearing lung carcinoma. 28 In this study, we generated human lung and colon cancer variants that express TAAs, survivin, or cep55, genetically lacking tapasin protein expression. To our knowledge, this study is first to demonstrate that CTL responses to endogenous TAAs presented by HLA class I molecules are significantly reduced to undetectable levels solely by the absence of tapasin.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…A defect in either component dramatically abrogates peptide loading of MHC-I, resulting in the destabilization of MHC-I complexes and, consequently, low surface MHC-I expression (30,31). TAP1 and TAP2 expression have been associated with the ability of DCs as well as macrophages to cross-present exogenous Ags (32,33). Furthermore, transduction of DCs to express elevated levels of TAP augments their ability to process Ag and results in increased display of viral peptides on surface MHC-I and a greater induction of virus-specific CD8 T cells (34).…”

Section: Discussionmentioning

confidence: 99%

Lung CD103+ Dendritic Cells Efficiently Transport Influenza Virus to the Lymph Node and Load Viral Antigen onto MHC Class I for Presentation to CD8 T Cells

Prabhu

Betts

et al. 2011

The Journal of Immunology

149

137

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The uptake, transport, and presentation of Ags by lung dendritic cells (DCs) are central to the initiation of CD8 T cell responses against respiratory viruses. Although several studies have demonstrated a critical role of CD11blow/negCD103+ DCs for the initiation of cytotoxic T cell responses against the influenza virus, the underlying mechanisms for its potent ability to prime CD8 T cells remain poorly understood. Using a novel approach of fluorescent lipophilic dye-labeled influenza virus, we demonstrate that CD11blow/negCD103+ DCs are the dominant lung DC population transporting influenza virus to the posterior mediastinal lymph node as early as 20 h postinfection. By contrast, CD11bhighCD103neg DCs, although more efficient for taking up the virus within the lung, migrate poorly to the lymph node and remain in the lung to produce proinflammatory cytokines instead. CD11blow/negCD103+ DCs efficiently load viral peptide onto MHC class I complexes and therefore uniquely possess the capacity to potently induce proliferation of naive CD8 T cells. In addition, the peptide transporters TAP1 and TAP2 are constitutively expressed at higher levels in CD11blow/negCD103+ DCs, providing, to our knowledge, the first evidence of a distinct regulation of the Ag-processing pathway in these cells. Collectively, these results show that CD11blow/negCD103+ DCs are functionally specialized for the transport of Ag from the lung to the lymph node and also for efficient processing and presentation of viral Ags to CD8 T cells.

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“…To our knowledge, defects in the expression and function of antigen-processing machinery (APM) genes may remarkably impair the processing of tumor-associated antigens (TAAs) and the presentation of TAA-derived peptides to CD8 + T cells, thereby providing malignant cells with an immune escape mechanism (6,7). On the basis of this information, we hope to develop a treatment strategy for OSCC that would prevent the escape of tumor cells from immunosurveillance and improve the efficacy of T-cell-based immunotherapy by restoring the normal expression of APM genes (8). Among the components of APM, transporters associated with antigen processing-1 (TAP-1) and the chaperon tapasin play important roles.…”

Section: Introductionmentioning

confidence: 99%

A novel approach to rescue immune escape in oral squamous cell carcinoma: Combined use of interferon-γ and LY294002

Wang

Pan²,

Jiang³

et al. 2010

Oncol Rep

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Abstract. Major histocompatibility complex (MHC) class I molecules have been found to be downmodulated in many tumors. The antigen-processing machinery (APM) genes, especially transporters associated with antigen processing (TAP)-1 and tapasin play important roles in the processing of class I antigens. In this study, we investigated the expression of TAP-1 and tapasin in oral squamous cell carcinoma (OSCC); the result indicated significant down-regulation in the expression of these genes. Interferon (IFN)-Á treatment was applied. After the addition of IFN-Á, unexpectedly, the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway was activated, which induced the proliferation of tumor cells. With the combined application of LY294002 (specific inhibitor of AKT signaling) and IFN-Á, tumor cell apoptosis was induced and the expression of TAP-1 and tapasin was still upregulated. Hence, our method is a novel and efficient approach to use IFN-Á for rescuing the cells from immunosurveillance.

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Combining the Antigen Processing Components TAP and Tapasin Elicits Enhanced Tumor-Free Survival

Cited by 39 publications

References 36 publications

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

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

Lung CD103+ Dendritic Cells Efficiently Transport Influenza Virus to the Lymph Node and Load Viral Antigen onto MHC Class I for Presentation to CD8 T Cells

A novel approach to rescue immune escape in oral squamous cell carcinoma: Combined use of interferon-γ and LY294002

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