Mass spectrometric identification of a naturally processed melanoma peptide recognized by CD8+ cytotoxic T lymphocytes.

Castelli, Chiara; Storkus, Walter J.; Maeurer, Markus; Martin, Dina M.; Huang, Eric C.; Pramanik, Birendra N.; Nagabhushan, Tattanahalli L.; Parmiani, Giorgio; Lotze, Michael T.

doi:10.1084/jem.181.1.363

Cited by 182 publications

(86 citation statements)

References 35 publications

(47 reference statements)

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“…28 Third, the Melan-A [26][27][28][29][30][31][32][33][34][35] /HLA-A2 epitope is generated and presented by HLA-A2 ϩ melanoma cells, and these are efficiently lysed by Melan-A [26][27][28][29][30][31][32][33][34][35] /HLA-A2-specific CTLs. 29 Finally, the Melan-A [26][27][28][29][30][31][32][33][34][35] /HLA-A2 epitope is generated by conventional proteasomes but may be destroyed by immunoproteasomes expressed by DCs or by interferon-␥ (IFN-␥)-treated tumor cells. 30 This final point makes the development of a Melan-A protein vaccine problematic as immunoproteasome-expressing DCs will fail to generate tumor-relevant CTLs in vivo, thus restricting the development of a Melan-A vaccine to peptide-based strategies, which have shown limited clinical efficacy because of multiple tumor escape mechanisms.…”

Section: Introductionmentioning

confidence: 99%

“…26 In contrast, Melan-A is unusual. First, a large proportion of healthy human leukocyte associated-A2 (HLA-A2)-restricted individuals possess naive CD8 ϩ T cells specific for the naturally presented Melan-A [26][27][28][29][30][31][32][33][34][35] /HLA-A2 epitope. 27 Second, the Melan-A [26][27][28][29][30][31][32][33][34][35] /HLA-A2 epitope is strikingly immunodominant with few other CD8 ϩ T-cell epitopes described.…”

Section: Introductionmentioning

confidence: 99%

“…First, a large proportion of healthy human leukocyte associated-A2 (HLA-A2)-restricted individuals possess naive CD8 ϩ T cells specific for the naturally presented Melan-A [26][27][28][29][30][31][32][33][34][35] /HLA-A2 epitope. 27 Second, the Melan-A [26][27][28][29][30][31][32][33][34][35] /HLA-A2 epitope is strikingly immunodominant with few other CD8 ϩ T-cell epitopes described. 28 Third, the Melan-A [26][27][28][29][30][31][32][33][34][35] /HLA-A2 epitope is generated and presented by HLA-A2 ϩ melanoma cells, and these are efficiently lysed by Melan-A [26][27][28][29][30][31][32][33][34][35] /HLA-A2-specific CTLs.…”

Section: Introductionmentioning

confidence: 99%

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Processing and cross-presentation of individual HLA-A, -B, or -C epitopes from NY-ESO-1 or an HLA-A epitope for Melan-A differ according to the mode of antigen delivery

Robson

McAlpine

Knights

et al. 2010

Blood

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The ability of dendritic cells (DCs) to cross-present protein tumor antigens to cytotoxic T lymphocytes (CTLs) underpins the success of therapeutic cancer vaccines. We studied cross-presentation of the cancer/testis antigen, NY-ESO-1, and the melanoma differentiation antigen, Melan-A by human DC subsets. Monocyte-derived DCs (MoDCs) efficiently cross-presented human leukocyte associated (HLA)–A2-restricted epitopes from either a formulated NY-ESO-1/ISCOMATRIX vaccine or when either antigen was mixed with ISCOMATRIX adjuvant. HLA-A2 epitope generation required endosomal acidification and was proteasome-independent for NY-ESO-1 and proteasome-dependent for Melan-A. Both MoDCs and CD1c+ blood DCs cross-presented NY-ESO-1–specific HLA-A2157-165–, HLA-B760-72–, and HLA-Cw392-100–restricted epitopes when formulated as an NY-ESO-1/ISCOMATRIX vaccine, but this was limited when NY-ESO-1 and ISCOMATRIX adjuvant were added separately to the DC cultures. Finally, cross-presentation of NY-ESO-1157-165/HLA-A2, NY-ESO-160-72/HLA-B7, and NY-ESO-192-100/HLA-Cw3 epitopes was proteasome-dependent when formulated as immune complexes (ICs) but only proteasome-dependent for NY-ESO-160-72/HLA-B7–restricted cross-presentation facilitated by ISCOMATRIX adjuvant. We demonstrate, for the first time, proteasome-dependent and independent cross-presentation of HLA-A–, B–, and C–restricted epitopes within the same full-length tumor antigen by human DCs. Our findings identify important differences in the capacities of human DC subsets to cross-present clinically relevant, full-length tumor antigens and how vaccine formulation impacts CTL responses in vivo.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Processing and cross-presentation of individual HLA-A, -B, or -C epitopes from NY-ESO-1 or an HLA-A epitope for Melan-A differ according to the mode of antigen delivery

Robson

McAlpine

Knights

et al. 2010

Blood

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“…22,23 Because massive numbers of tumor cells and CTL are needed for this technique, however, it remained unpublished for pancreatic cancer. This problem might be circumvented by utilizing mice for establishing new pancreatic cancer cell lines, though sufficient experience with pancreatic cancer cells makes the establishment of new cell lines easier.…”

Section: Hla-a2 Is 1 Restriction Element In Recognition Of Pancreaticmentioning

confidence: 99%

Cytotoxic T lymphocyte mediated recognition of human pancreatic cancer cells

Peiper

Sato

Streichert

et al. 2002

Intl Journal of Cancer

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T lymphocytes play an important role in tumor rejection and their response to human malignant melanoma has been well documented. In contrast, the existence of cytotoxic T lymphocytes (CTL) to pancreatic cancer remains unclear. Tumor-associated lymphocytes (TAL) and peripheral blood monocytes (PBMC) were isolated from pancreatic cancer patients. Tumor-specific CTL were generated from TAL and PBMC using solid-phase anti-CD3, low-dose IL-2 (50 IU/ml) and repetitive autologous tumor stimulation. The specificity of CTL was tested in standard cytotoxicity assays using autologous tumor cells, autologous fibroblasts when available, several allogeneic pancreatic tumor cells and the NK-sensitive cell line K562. Anti-HLA-Class I MAb, W6/32, was used to demonstrate that tumor-specific CTL were HLA-Class I restricted. HLA-molecules of human pancreatic cancer cells were washed out using acid elution. Eight consecutive, histologically confirmed pancreatic cancer specimen as well as peripheral blood mononuclear cells were analyzed. Pancreatic cancer remains the fifth leading cause of malignant death in Western countries. Despite advances in surgical and non-surgical treatment, this tumor has an overall 5-year survival rate of 3-5%, in selected series of resected tumors an overall survival of up to 30% can be achieved. 1 New treatment efforts are undertaken to control pancreatic cancer including biologic therapies with monoclonal antibodies or cytokines. 2 Cellular immunotherapy and possible vaccine strategies, nevertheless, have been studied scarcely.In recent years, immune response of cytotoxic T lymphocytes (CTL) to human tumors such as malignant melanoma, 3 ovarian cancer and breast cancer 4 have been shown, but little is known about the immune response to pancreatic cancer. In general, HLAClass I restricted recognition of tumor cells by CD8 ϩ cytotoxic T lymphocytes is reported, leading to the identification of tumor specific antigens (TA) and tumor associated antigens (TAA) for several carcinomas. Several clinical trials are being performed using cancer vaccines. The approach of generating CTL in pancreatic cancer, however, has been a limited focus of interest so far, though this might lead to novel therapeutic strategies such as peptide vaccination, because T cell mediated specific immunity plays a central role in tumor rejection. Therefore, it is important to know whether HLA-Class I restricted and tumor specific CTL can be established in pancreatic cancer. MATERIAL AND METHODS PatientsEight consecutive patients (PANK1-PANK8) with histologically confirmed adenocarcinoma of the pancreas were included in our study. Specimens were obtained through the Department of General Surgery, University Hospital Hamburg-Eppendorf, under approval of the institutional review board. None of the patients had received chemotherapy and tumor materials were collected from the patients' initial operation in all cases. In 6 cases, primary pancreatic tumor tissue could be obtained, whereas in 1 patient each a metastatic lymph node or malignant ...

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“…To date, with the exception of melanoma (Castelli et al, 1996;Cox et al, 1994), there is limited information on the intrinsic immunogenicity or the identity and density of antigenic peptides and CTL epitopes presented by the majority of spontaneously arising human tumours. However, in the last few years several reports have shown that multiple epitopes can be recognized by T cells on several human tumours (i.e.…”

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confidence: 99%

Induction of tumour-specific CD8+ cytotoxic T lymphocytes by tumour lysate-pulsed autologous dendritic cells in patients with uterine serous papillary cancer

et al. 2002

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Uterine serous papillary carcinoma is a highly aggressive variant of endometrial cancer histologically similar to high grade ovarian cancer. Unlike ovarian cancer, however, it is a chemoresistant disease from onset, with responses to combined cisplatinum-based chemotherapy in the order of 20% and an extremely poor prognosis. In this study, we demonstrate that tumour lysate-pulsed autologous dendritic cells can elicit a specific CD8 + cytotoxic T lymphocyte response against autologous tumour target cells in three patients with uterine serous papillary cancer. CTL from patients 1 and 2 expressed strong cytolytic activity against autologous tumour cells, did not lyse autologous lymphoblasts or autologous EBV-transformed cell lines, and were variably cytotoxic against the NK-sensitive cell line K-562. Patient 3 CD8 + T cells expressed a modest but reproducible cytotoxicity against autologous tumour cells only at the time of the first priming. Further priming attempts with PBL collected from patient 3 after tumour progression in the lumboaortic lymph nodes were unsuccesful. Cytotoxicity against autologous tumour cells could be significantly inhibited by anti-HLA class I (W6/32) and anti-LFA-1 MAbs. Highly cytotoxic CD8 + T cells from patients 1 and 2 showed a heterogeneous CD56 expression while CD56 was not expressed by non-cytotoxic CD8 + T cells from patient 3. Using two colour flow cytometric analysis of intracellular cytokine expression at the single cell level, a striking dominance of IFN-g expressors was detectable in CTL populations of patients 1 and 2 while in patient 3 a dominant population of CD8 + T cells expressing IL-4 and IL-10 was consistently detected. Taken together, these data demonstrate that tumour lysate-pulsed DC can be an effective tool in inducing uterine serous papillary cancer-specific CD8 + CTL able to kill autologous tumour cells in vitro. However, high levels of tumour specific tolerance in some patients may impose a significant barrier to therapeutic vaccination. These results may have important implications for the treatment in the adjuvant setting of uterine serous papillary cancer patients with active or adoptive immunotherapy.

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Mass spectrometric identification of a naturally processed melanoma peptide recognized by CD8+ cytotoxic T lymphocytes.

Cited by 182 publications

References 35 publications

Processing and cross-presentation of individual HLA-A, -B, or -C epitopes from NY-ESO-1 or an HLA-A epitope for Melan-A differ according to the mode of antigen delivery

Processing and cross-presentation of individual HLA-A, -B, or -C epitopes from NY-ESO-1 or an HLA-A epitope for Melan-A differ according to the mode of antigen delivery

Cytotoxic T lymphocyte mediated recognition of human pancreatic cancer cells

Induction of tumour-specific CD8+ cytotoxic T lymphocytes by tumour lysate-pulsed autologous dendritic cells in patients with uterine serous papillary cancer

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