MHC class I‐deficient metastatic tumor variants immunoselected by T lymphocytes originate from the coordinated downregulation of APM components

García-Lora, Angel; Martínez, M.; Algarra, Ignacio; Gaforio, José J.; Garrido, Federico

doi:10.1002/ijc.11241

Cited by 80 publications

(63 citation statements)

References 25 publications

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“…It is an intriguing and consistent finding that Tpn is downregulated in many human carcinomas, such as breast cancer (8,9), melanoma (10), colorectal carcinoma (11), and both small cell and non -small cell lung carcinoma (12), as well as mouse cancers, such as mouse fibrosarcoma (13) and mouse melanoma (14). Remarkably, in human colorectal cancers, Tpn is more frequently lost than TAP1, LMP2, and LMP7 (11), suggesting that the loss of Tpn could be a key event in overcoming immune surveillance in these tumors.…”

mentioning

confidence: 86%

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

Lou

Basha²,

Seipp³

et al. 2008

Clinical Cancer Research

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Purpose: Tpn is a member of the MHC class I loading complex and functions to bridge the TAP peptide transporter to MHC class I molecules. Metastatic human carcinomas often express low levels of the antigen-processing components Tapasin and TAP and display few functional surface MHC class I molecules. As a result, carcinomas are unrecognizable by effector CTLs. The aim of this study is to examine if Tapasin (Tpn) plays a critical role in the escape of tumors from immunologic recognition. Experimental Design: To test our hypothesis, a nonreplicating adenovirus vector encoding human Tpn (AdhTpn) was constructed to restore Tpn expression in vitro and in vivo in a murine lung carcinoma cell line (CMT.64) that is characterized by down-regulation of surface MHC class I due to deficiency in antigen-processing components. Results: Ex vivo, Tpn expression increased surface MHC class I and restored susceptibility of tumor cells to antigen-specific CTL killing, and AdhTpn infection of dendritic cells also significantly increased cross-presentation and cross-priming. Furthermore, tumor-bearing animals inoculated with AdhTpn demonstrated a significant increase in CD8 + and CD4 + T cells and CD11c + dendritic cells infiltrating the tumors. Provocatively, whereas syngeneic mice bearing tumors that were inoculated with AdhTpn a significant reduction in tumor growth and increased survival compared with vector controls, combining AdhTpn inoculation with AdhTAP1resulted in a significant augmentation of protection from tumor-induced death than either component alone. Conclusions: This is the first demonstration that Tpn alone can enhance survival and immunity against tumors but additionally suggests that Tpn and TAP should be used together as components of immunotherapeutic vaccine protocols to eradicate tumors.

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confidence: 86%

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

Lou

Basha²,

Seipp³

et al. 2008

Clinical Cancer Research

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“…β2m is an integral component, of MHC class I expression, is synthesized in the CNS, and plays a critical role in neural development. (42) Many tumors, including brain tumors, are known to down regulate class I MHC expression to avoid immune surveillance. (42) Although the extent of this surveillance for CNS-localized malignancies is unclear, the fact that β2m is up-regulated in the context of MHC class I down-regulation suggests that it may be a positive feedback mechanism or pro-tumorigenic function.…”

Section: Validation Of Previously Identified and Discovery Of New Bimentioning

confidence: 99%

“…(42) Many tumors, including brain tumors, are known to down regulate class I MHC expression to avoid immune surveillance. (42) Although the extent of this surveillance for CNS-localized malignancies is unclear, the fact that β2m is up-regulated in the context of MHC class I down-regulation suggests that it may be a positive feedback mechanism or pro-tumorigenic function. (43,44) The latter hypothesis is supported by recent findings about β2m tumor promoting activities in prostate cancer through activation of osteogenic proteins, (45) some of which, including SPARC, are also seen in our analysis.…”

Section: Validation Of Previously Identified and Discovery Of New Bimentioning

confidence: 99%

Proteomic Identification of Biomarkers in the Cerebrospinal Fluid (CSF) of Astrocytoma Patients

et al. 2007

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The monitoring of changes in the protein composition of the cerebrospinal fluid (CSF) can be used as a sensitive indicator of central nervous system (CNS) pathology, yet its systematic application to analysis of CNS neoplasia has been limited. There is a pressing need for both a better understanding of gliomagenesis, and the development of reliable biomarkers of the disease. In this report, we used two proteomic techniques, two-dimensional gel electrophoresis (2-DE) and cleavable Isotope-Coded Affinity Tag (cICAT), to compare CSF proteomes in order to identify tumor and grade specific biomarkers in patients bearing brain tumors of differing histologies and grades. Retrospective analyses were performed on 60 samples derived from astrocytomas WHO grade II, III and IV, schwannomas, metastastic brain tumors, inflammatory samples and non-neoplastic controls. We identified 103 potential tumor-specific markers; of which 20 were high-grade astrocytoma-specific. These investigations allowed us to identify a spectrum of signature proteins that could differentiate *Address for Correspondence/Reprints: Erwin G. Van Meir, Ph.D, Winship Cancer Institute, Emory University, 1365C Clifton Rd. N.E, C5078, Atlanta, GA 30322, Phone: 404-778-5563, Fax: 404-778-5550, e-mail: evanmei@emory.edu. Significance: The measurement of alterations in the protein composition of the cerebrospinal fluid (CSF) can be used as a sensitive indicator of central nervous system (CNS) pathology, yet its systematic application to analysis of CNS neoplasia has been limited. There is a pressing need for both a better understanding of gliomagenesis, and the development of reliable biomarkers of the disease. Our investigations allowed us to identify a spectrum of signature proteins that could differentiate between low (AII) and high-grade (AIV) astrocytoma that warrant further validation as potential new markers for diagnosis, prognosis and disease follow-up . These candidate biomarkers may also have functional properties that play a critical role in the development and malignant progression of human astrocytomas, thus possibly representing novel therapeutic targets for this highly lethal disease.Author contributions Project concept and experimental designs were developed by EGVM and FWK. All experiments were perfomed by FWK with the following exceptions; Mass spectrometry and cICAT were done by MSR. BJS performed the statistical analysis, JP provided expertise with proteomic analyses; JJO, MDG, AG, SK and GYG all provided CSF samples. FWK and EGVM interpreted the results and wrote the manuscript. All authors read the manuscript. NIH Public Access

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“…However, whether MHC class I molecules have a positive or negative role in tumor patients' survival remains controversial. Certain studies have reported that MHC class I loss has poor outcomes due to its impact on antigen presentation to T-lymphocytes and CTLs (5,6). By contrast, other reports have revealed that MHC class I loss may improve patients' survival through activating natural killer (NK) cell function (7,8).…”

Section: Introductionmentioning

confidence: 99%

NLRC5 expression in tumors and its role as a negative prognostic indicator in stage III non-small-cell lung cancer patients

Guo

Liu

et al. 2015

Oncology Letters

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Abstract. Major histocompatibility complex (MHC) class I molecules have a crucial role in tumor immune evasion; however, the association of MHC class I molecules with outcomes in cancer patients remains controversial. Nucleotide-binding oligomerization-like receptor family caspase recruitment domain-containing 5 (NLRC5) has been reported to be a MHC class I transactivator. However, the expression and function of NLRC5 in cancer remains to be elucidated. The present study aimed to retrospectively examine NLRC5 expression in human tumor tissues and its association with clinical outcomes of non-small-cell lung cancer (NSCLC) stage III patients. The expression of MHC class I and NLRC5 in NSCLC were detected using immunohistochemistry (IHC). The association between their expression levels was assessed using the Pearson's χ 2 test and their association with survival was assessed using Kaplan-Meier analysis and the log-rank test. In addition, the expression of NLRC5 and MHC class I were examined in 323 cases of seven other types of tumors and their correlations were studied. The results revealed that the expression of NLRC5 was correlated with that of MHC class I in NSCLC patients (P=0.008). MHC class I-positive and nuclear NLRC5-positive NSCLC patients were found to have shorter overall survival (OS) rates (log-rank, P=0.032 and P=0.039, respectively). In addition, in the seven different tumor types, there was a significant correlation between MHC class I and NLRC5 nuclear expression (P<0.001) as well as MHC class I and NLRC5 cytoplasmic expression (P=0.003). In conclusion, NLRC5 was demonstrated to be widely expressed in eight tumor tissues and its expression was correlated with that of MHC class I. Of note, nuclear NLRC5-negative and MHC class I-negative stage III NSCLC patients had improved OS rates compared to those with positive expression. Therefore, NLRC5 and MHC class I may be negative prognostic indicators in NSCLC stage III patients.

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MHC class I‐deficient metastatic tumor variants immunoselected by T lymphocytes originate from the coordinated downregulation of APM components

Cited by 80 publications

References 25 publications

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

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

Proteomic Identification of Biomarkers in the Cerebrospinal Fluid (CSF) of Astrocytoma Patients

NLRC5 expression in tumors and its role as a negative prognostic indicator in stage III non-small-cell lung cancer patients

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