Peptide‐specific CD8+ T‐cell evolution <i>in vivo</i>: Response to peptide vaccination with Melan‐A/MART‐1

Jäger, Elke; Höhn, H.; Necker, Artje; Förster, Reinhold; Karbach, Julia; Freitag, Kirsten; Neukirch, Claudia; Castelli, Chiara; Salter, Russell D.; Knuth, A.; Maeurer, Markus

doi:10.1002/ijc.10165

Cited by 61 publications

(36 citation statements)

References 54 publications

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“…Because certain TCR Vh restrictions are often shared in patients with the same type of cancer, as determined by a sensitive spectratyping for the TCR Vh variable complementarity-determining region 3, it has been suggested that they represent expansions of TA-specific T cells (4 -7). In some cases, TA specificity of such TCR Vhrestricted T cells has been confirmed (24,25). A more recent analysis suggests that TCR Vh profiles in patients with cancer reflect expansions of clonal as well as non -clonal-reactive T cells (26), and that contractions of TCR Vh-restricted T cells are common.…”

Section: Discussionmentioning

confidence: 99%

Alterations in the T-Cell Receptor Variable β Gene–Restricted Profile of CD8+ T Lymphocytes in the Peripheral Circulation of Patients with Squamous Cell Carcinoma of the Head and Neck

Albers

Visús

Tsukishiro

et al. 2006

Clinical Cancer Research

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Purpose: Apoptosis of activated CD8 + Tcells is often seen in tumor-infiltrating lymphocytes and circulating peripheral blood mononuclear cells (PBMC) in patients with squamous cell carcinoma of the head and neck (SCCHN). We investigated whether T-cell receptor (TCR) variable h chain (Vh)^restricted Tcells were more sensitive to apoptosis than non^TCR Vh-restricted Tcells. Experimental Design: Flow cytometry analysis with anti-TCR Vhantibodies was used to define expansions and contractions of Vh-restricted T cells in patients with SCCHN relative to normal donors. This staining was combined with AnnexinV binding to indicate earlyT-cell apoptosis. Results: The TCR Vh profiles of CD3 + T cells in tumor-infiltrating lymphocytes and PBMCs of patients with SCCHN were altered relative to controls, with one to five expansions and numerous contractions of TCR Vh-restricted T cells detected. These types of alterations were significantly greater in CD8 + than CD4 + T cells. Enhanced Annexin V binding to CD8 + T cells was evident in PBMCs obtained from all patients, with 3 of 13 showing preferential targeting for apoptosis of TCR Vh-restricted Tcells. Conclusions: TCR Vh profiles of CD8 + T cells were altered in patients with SCCHN relative to normal controls. This may reflect increased apoptosis of expanded or contracted CD8 + T cells, which define theTCR Vh profile of antigen-responsiveT-cell populations in patients with cancer.

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Section: Discussionmentioning

confidence: 99%

Alterations in the T-Cell Receptor Variable β Gene–Restricted Profile of CD8+ T Lymphocytes in the Peripheral Circulation of Patients with Squamous Cell Carcinoma of the Head and Neck

Albers

Visús

Tsukishiro

et al. 2006

Clinical Cancer Research

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“…0, 2 and 16 weeks after initiation of therapy). Frozen PBMC were thawed for tetramer staining as described [11]. All MoAb were from Beckman/Coulter, Krefeld, Germany.…”

Section: Methodsmentioning

confidence: 99%

“…CD4 + T cells were enriched from 3-5 · 10 7 PMBC using anti-CD8-coated immunomagnetic beads (Miltenyi, Bergisch Gladbach, Germany). The CD4 + , CD8-depleted PBMC population was incubated with the respective PE-labelled tetramer reagents (1 lg of tetramer/2 · 10 7 cells) for 2 h, washed once, and incubated for 15 min with an anti-PE-directed MoAb attached to immunomagnetic beads (Miltenyi, Bergisch Gladbach, Germany) as previously described [11]. Tetramer-sorted cells were exposed to autologous macrophages which had been infected either with M. tuberculosis or with Mycobacterium avium intracellulare as described in detail [19] for 72 h. The anti-DR-specific MoAb L243 was used to block MHC class II-restricted T-cell recognition of naturally processed and presented antigens, while the anti-MHC class I-specific MoAb w6/32 was used as a negative control.…”

Section: Methodsmentioning

confidence: 99%

MHC class II Tetramer Guided Detection of Mycobacterium tuberculosis‐specific CD4⁺ T Cells in Peripheral Blood from Patients with Pulmonary Tuberculosis

Höhn¹,

Kortsik²,

Zehbe³

et al. 2007

Scand J Immunol

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Novel diagnostic tools are needed to diagnose latent infection and to provide biologically meaningful surrogate markers to define cellular immune responses against Mycobacterium tuberculosis (MTB). Interferon gamma‐based assays have recently been developed in addition to the more than 100‐year‐old tuberculin skin test (TST) for the immune diagnosis of MTB in blood. The advent of soluble MHC/peptide tetramer molecules allows to objectively enumerate antigen‐specific T cells. We identified novel MHC class II‐restricted MTB epitopes and used HLA‐DR4 tetrameric complexes to visualize ex vivo CD4+ T cells directed against the antigens Ag85B and the 19‐kDa lipoprotein, shared between MTB and other Mycobacterium species, and CD4+ T cells which recognize the MTB‐associated ESAT‐6 antigen. MTB‐reactive CD4+ T cells reside predominantly in the CD45RA+ CD28+ and CD45− CD28+ T‐cell subset and recognize naturally processed and presented MTB epitopes. HLA‐DR4‐restricted, Ag85B or ESAT‐6‐specific CD4+ T cells show similar dynamics over time in peripheral blood mononuclear cells (PBMC) when compared with CD8+ T cells directed against the corresponding HLA‐A2‐presented MTB epitopes in patients with pulmonary MTB infection and subsequent successful therapy. This was not found to be true for T‐cell responses directed against the 19‐kDa lipoprotein. The dissection of the cellular immune response in M. tuberculosis infection will enable novel strategies for monitoring MTB vaccine candidates and to gauge CD4+ T cells directed against MTB.

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“…Although the immunogenicity of a number of TAA has been documented in clinical trials, their therapeutic potential has not been clearly assessed, with the exception of the Melan-A/MART-1 antigen. Indeed, the therapeutic usefulness of the Melan-A antigen in melanoma is supported by the analysis of several active [2,3] and passive [4][5][6][7][8][9] immunotherapy protocols targeting this antigen.…”

Section: Introductionmentioning

confidence: 99%

Frequent occurrence of high affinity T cells against MELOE‐1 makes this antigen an attractive target for melanoma immunotherapy

et al. 2010

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We recently showed that the infusion of tumor infiltrating lymphocytes specific for the MELOE-1 antigen was associated with a prolonged relapse-free survival for HLA-A2 1 melanoma patients who received tumor infiltrating lymphocytes therapy. Here, we characterized the MELOE-1/A2-specific T-cell repertoire in healthy donors and melanoma patients to further support an immunotherapy targeting this epitope. Using tetramer enrichment followed by multicolor staining, we found that MELOE-1-specific T cells were present in the blood of healthy donors and patients at similar frequencies (around 1 in 1 Â 10 5 CD8 1 cells). These cells mainly displayed a naïve phenotype in 4/6 healthy donors and 3/6 patients, whereas high proportions of memory cells were observed in the remaining individuals of both groups. There was a recurrent usage of the Va12.1 chain for 17/18 MELOE-1-specific T-cell clones derived from healthy donors or patients, associated with diverse Vb chains and V(D)J junctional sequences. All clones derived from melanoma patients (9/9) were reactive against the MELOE-1 36-44 peptide and against HLA-A2 1 melanoma cell lines. This study documents the existence of a large TCR repertoire specific for the MELOE-1/A2 epitope and its capacity to give rise to antitumor CTL that supports the development of immunotherapies targeting this epitope.Key words: Immunotherapy . Melanoma . MELOE-1 . T-cell repertoire . TCR Introduction A key advance in tumor immunology in the past 15 years has been the elucidation of the antigenic basis of tumor cell recognition and destruction, which has opened the way to development of antigen-based immunotherapy in cancer patients. Tumor-associated antigens (TAA) have been grouped into categories according to their expression pattern in neoplastic and normal tissues. TAA can be roughly subdivided into two main classes: proteins expressed specifically by tumor cells, and proteins that are expressed by both tumor cells and by normal cells to a significant level. The first category includes cancergermline antigens, proteins expressed by unconventional gene expression and mutated antigens (see [1] for review). TAA belonging to the second category are the differentiation antigens, mainly expressed in the melanocytic lineage, and the antigens overexpressed by various tumor tissues. Although the immunogenicity of a number of TAA has been documented in clinical Ã These authors contributed equally to this work. We recently showed a correlation between the infusion of T cells reactive against an HLA-A2 epitope derived from another melanoma antigen, MELOE-1, and time to progression of patients treated with autologous tumor infiltrating lymphocytes (TIL) [10]. This antigen is encoded by the meloe gene, overexpressed in human melanoma cell lines, when compared to normal melanocytes, and dramatically underexpressed in other cancer cell lines (colon, renal, breast and lung carcinoma cell lines) and in a variety of normal tissues [10]. This expression profile and the potential involvement of MELOE-1-specific...

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Peptide‐specific CD8+ T‐cell evolution in vivo: Response to peptide vaccination with Melan‐A/MART‐1

Abstract: Monitoring of CD8؉ T-cell responses in cancer patients

Cited by 61 publications

References 54 publications

Alterations in the T-Cell Receptor Variable β Gene–Restricted Profile of CD8+ T Lymphocytes in the Peripheral Circulation of Patients with Squamous Cell Carcinoma of the Head and Neck

Alterations in the T-Cell Receptor Variable β Gene–Restricted Profile of CD8+ T Lymphocytes in the Peripheral Circulation of Patients with Squamous Cell Carcinoma of the Head and Neck

MHC class II Tetramer Guided Detection of Mycobacterium tuberculosis‐specific CD4⁺ T Cells in Peripheral Blood from Patients with Pulmonary Tuberculosis

Frequent occurrence of high affinity T cells against MELOE‐1 makes this antigen an attractive target for melanoma immunotherapy

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Peptide‐specific CD8+ T‐cell evolution in vivo: Response to peptide vaccination with Melan‐A/MART‐1

Abstract: Monitoring of CD8؉ T-cell responses in cancer patients

Cited by 61 publications

References 54 publications

Alterations in the T-Cell Receptor Variable β Gene–Restricted Profile of CD8+ T Lymphocytes in the Peripheral Circulation of Patients with Squamous Cell Carcinoma of the Head and Neck

Alterations in the T-Cell Receptor Variable β Gene–Restricted Profile of CD8+ T Lymphocytes in the Peripheral Circulation of Patients with Squamous Cell Carcinoma of the Head and Neck

MHC class II Tetramer Guided Detection of Mycobacterium tuberculosis‐specific CD4+ T Cells in Peripheral Blood from Patients with Pulmonary Tuberculosis

Frequent occurrence of high affinity T cells against MELOE‐1 makes this antigen an attractive target for melanoma immunotherapy

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MHC class II Tetramer Guided Detection of Mycobacterium tuberculosis‐specific CD4⁺ T Cells in Peripheral Blood from Patients with Pulmonary Tuberculosis