The Human T Cell Response to Melanoma Antigens

Romero, Pedro; Cerottini, Jean‐Charles; Speiser, Daniel E.

doi:10.1016/s0065-2776(06)92005-7

Cited by 64 publications

(53 citation statements)

References 219 publications

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“…The presence of antitumor cellular responses, humoral responses, or both to tumorassociated antigens (TAs) has been observed in many, but not all, patients with cancer. 1,2 The evidence for such pre-existing antitumor immunity in patients with cancer confirms that the tumor-bearing host is capable of mounting an immune response to TAs. Tumor progression from a single transformed cell to a mass of malignant cells is a multistep process involving a series of genetic changes occurring in human subjects over a period of months or years and culminating in the established tumor.…”

Section: Introductionmentioning

confidence: 87%

“…If the tricks tumors use for protection from immune intervention by the host are responsible for their progression, then it could be surmised that a limited success of current immune therapies for cancer can be reversed by therapies that target the escape mechanisms, and because these escape mechanisms might be unique for each tumor rather than generalized, the future challenge will be to identify the "immunologic signature" of each tumor and then use selective therapies to eliminate the tricks and restore vigorous antitumor immunity. 1,13,14 Furthermore, the frequency of such peptidespecific T cells appears to be higher in the circulation of patients with cancer than in healthy subjects. 15 Finally, the SEREX technology, based on the presence of tumor-specific antibodies in sera of patients with cancer, has been successfully used for tumor-antigen discovery in many laboratories.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…More recent experiments, using tetramers and flow cytometry, have directly demonstrated the presence of tumor peptide-specific T cells in the circulation of patients with cancer. 1,13,14 Furthermore, the frequency of such peptidespecific T cells appears to be higher in the circulation of patients with cancer than in healthy subjects. 15 Finally, the SEREX technology, based on the presence of tumor-specific antibodies in sera of patients with cancer, has been successfully used for tumor-antigen discovery in many laboratories.…”

Section: Tumor Progression and The Host Immune Responsementioning

confidence: 99%

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Immune responses to malignancies

2010

Journal of Allergy and Clinical Immunology

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Immune responses to tumor-associated antigens (TAs) are often detectable in tumor-bearing hosts, but they fail to eliminate malignant cells or prevent the development of metastases. Patients with cancer generate robust immune responses to infectious agents (bacteria and viruses) perceived as a "danger signal" but only ineffective weak responses to TAs, which are considered as "self." This fundamental difference in responses to self versus nonself is further magnified by the ability of tumors to subvert the host immune system. Tumors induce dysfunction and apoptosis in CD8 + antitumor effector cells and promote expansion of regulatory T cells, myeloid-derived suppressor cells, or both, which downregulate antitumor immunity, allowing tumors to escape from the host immune system. The tumor escape is mediated by several distinct molecular mechanisms. Recent insights into these mechanisms encourage expectations that a more effective control of tumorinduced immune dysfunction will be developed in the near future. Novel strategies for immunotherapy of cancer are aimed at the protection and survival of antitumor effector cells and also of central memory T cells in the tumor microenvironment. KeywordsCancer; immunity; tumor escape; immune suppression; effector T cells Evidence accumulated over the last few years convincingly shows that the host immune system is involved in cancer development and progression, as well as control of metastasis. The presence of antitumor cellular responses, humoral responses, or both to tumorassociated antigens (TAs) has been observed in many, but not all, patients with cancer. 1,2 The evidence for such pre-existing antitumor immunity in patients with cancer confirms that the tumor-bearing host is capable of mounting an immune response to TAs. Tumor progression from a single transformed cell to a mass of malignant cells is a multistep process involving a series of genetic changes occurring in human subjects over a period of months or years and culminating in the established tumor. 3 During this period, neither the host immune system nor the developing tumor are idle: those newly emerging tumor cells that are recognized by the immune system are eliminated only to be replaced by genetic tumor variants resistant to immune intervention and giving rise to a heterogenous population of malignant cells found in any tumor. Tumors are genetically unstable, and the emergence of new genetic variants, which is responsible for the tumor heterogeneity, ensures that the tumor survives in the face of the host immune system. Only the tumor cells that manage to avoid recognition escape and survive, whereas those that are recognized by the immune system are eliminated as soon as they arise. The tumor development involves a prolonged NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript series of checks and balances between the host attempting to curtail tumor growth and the tumor benefiting from genetic changes, altering its microenvironment and avoiding immune elimination. Thus the...

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Section: Introductionmentioning

confidence: 87%

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Section: Tumor Progression and The Host Immune Responsementioning

confidence: 99%

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Immune responses to malignancies

2010

Journal of Allergy and Clinical Immunology

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Section: Introductionmentioning

confidence: 99%

“…The melanocyte differentiation antigens include tyrosinase, gp100/Pmel17, Melan-A/Mart-1, and tyrosinase-related protein-1 and 2. Peptides derived from these proteins are presented on the surface of cells in association with MHC class I molecules, and induce T-cell responses in melanoma patients [6].Tyrosinase is a copper-binding enzyme that catalyzes the ratelimiting reaction in melanin synthesis; it is a membrane-associated N-linked glycoprotein synthesized and folded in the endoplasmic reticulum (ER), and subsequently transported via the trans-Golgi network to melanosomes, where melanin is synthesized [7].Loss of pigmentation is common in human melanoma cells. In amelanotic melanoma cell lines, tyrosinase fails to reach the melanosome, and is retained in the ER due to acidification of the ER-Golgi boundary that is hostile to its maturation [8,9].…”

mentioning

confidence: 99%

Melanoma cells present high levels of HLA‐A2‐tyrosinase in association with instability and aberrant intracellular processing of tyrosinase

Michaeli

Sinik²,

Haus-Cohen³

et al. 2012

Eur J Immunol

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Short-lived protein translation products are proposed to be a major source of substrates for major histocompatibility complex (MHC) class I antigen processing and presentation; however, a direct link between protein stability and the presentation level of MHC class I-peptide complexes has not been made. We have recently discovered that the peptide Tyr (369-377) , derived from the tyrosinase protein is highly presented by HLA-A2 on the surface of melanoma cells. To examine the molecular mechanisms responsible for this presentation, we compared characteristics of tyrosinase in melanoma cells lines that present high or low levels of HLA-A2-Tyr (369-377) complexes. We found no correlation between mRNA levels and the levels of HLA-A2-Tyr (369-377) presentation. Co-localization experiments revealed that, in cell lines presenting low levels of HLA-A2-Tyr (369-377) complexes, tyrosinase co-localizes with LAMP-1, a melanosome marker, whereas in cell lines presenting high HLA-A2-Tyr (369-377) levels, tyrosinase localizes to the endoplasmic reticulum. We also observed differences in tyrosinase molecular weight and glycosylation composition as well as major differences in protein stability (t 1/2 ). By stabilizing the tyrosinase protein, we observed a dramatic decrease in HLA-A2-tyrosinase presentation. Our findings suggest that aberrant processing and instability of tyrosinase are responsible for the high presentation of HLA-A2-Tyr (369-377) complexes and thus shed new light on the relationship between intracellular processing, stability of proteins, and MHC-restricted peptide presentation.Keywords: Class I MHC processing and presentation r TCR-like antibody r Tumor antigens r Tumor immunology r Tyrosinase IntroductionThe source of major histocompatibility complex (MHC) class I peptides has been extensively investigated. The major source of MHC class I peptides are proteins that are never folded correctly due to errors in transcriptional, translational, or posttranslational processes and as such include defective ribosome products (DRiPs) [1]. The MHC class I Ag processing pathway mainly samples newly synthesized proteins as adding Correspondence: Dr. Yoram Reiter e-mail: reiter@tx.technion.ac.il protein synthesis inhibitor to cells almost abolishes the binding of peptides to the transporter associated with antigen presentation (TAP) [2]. Sampling newly synthesized proteins is important for rapid presentation to the immune system that may be critical when cells are infected with a virus; indeed, even though most viral proteins are very stable, presentation of viral-derived peptides on MHC class I molecules and lysis of viral-infected cells is observed within approximately 1 h postinfection [3,4].Proteasomes create antigenic peptides from distinct proteins at different efficiencies: rapidly degraded newly synthesized proteins which represent the DRiPs, the major substrate for MHC class I peptide presentation, which are typically degraded within 10 min of synthesis, and a slower degraded pool of proteins thatwww.eji-journal....

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Promises and Challenges with Immunomodulatory Biologics

Ponce

2014

Molecular Immunotoxicology

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The Human T Cell Response to Melanoma Antigens

Cited by 64 publications

References 219 publications

Immune responses to malignancies

Immune responses to malignancies

Melanoma cells present high levels of HLA‐A2‐tyrosinase in association with instability and aberrant intracellular processing of tyrosinase

Promises and Challenges with Immunomodulatory Biologics

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