Multiple HLA Class II-Restricted Melanocyte Differentiation Antigens Are Recognized by Tumor-Infiltrating Lymphocytes from a Patient with Melanoma

Robbins, Paul F.; El‐Gamil, Mona; Li, Yong F.; Zeng, Gang; Dudley, Mark E.; Rosenberg, Steven A.

doi:10.4049/jimmunol.169.10.6036

Cited by 70 publications

(49 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In few human tumor models, multiple antigens recognized by autologous T cell responses were stepwise identified over time (26,(33)(34)(35). In each case, a rather individual set of both shared and mutated antigens was targeted by T cells, which is in line with the findings reported herein.…”

Section: Discussionsupporting

confidence: 78%

The response of autologous T cells to a human melanoma is dominated by mutated neoantigens

Lennerz

Fatho²,

Gentilini³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

418

318

View full text Add to dashboard Cite

Our understanding of pathways leading to antitumor immunity may depend on an undistorted knowledge of the primary antigenic targets of patients' autologous T cell responses. In the melanoma model derived from patient DT, we applied cryopreserved shortterm autologous mixed lymphocyte-tumor cell cultures (MLTCs) in combination with an IFN-␥ enzyme-linked immunospot (ELISPOT) assay to cDNA expression screening. We identified three previously unknown peptides processed from melanosomal proteins tyrosinase (presented by HLA-A*2601 and -B*3801) and gp100 (presented by HLA-B*07021) and five neoantigens generated by somatic point mutations in the patient's melanoma. The mutations were found in the genes SIRT2, GPNMB, SNRP116, SNRPD1, and RBAF600. Peptides containing the mutated residues were presented by HLA-A*03011, -B*07021, and -B*3801. Mutation-induced functional impairment was so far demonstrated for SIRT2. Within MLTC responder populations that were independently expanded from the patient's peripheral blood lymphocytes of different years, T cells against mutated epitopes clearly predominated. These results document a high degree of individuality for the cellular antitumor response and support the need for individualizing the monitoring and therapeutic approaches to the primary targets of the autologous T cell response, which may finally lead to a more effective cancer immunotherapy.expression cloning ͉ peptide ͉ tumor antigen ͉ mixed lymphocyte-tumor cell culture ͉ cytotoxic T lymphocytes

show abstract

Section: Discussionsupporting

confidence: 78%

The response of autologous T cells to a human melanoma is dominated by mutated neoantigens

Lennerz

Fatho²,

Gentilini³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

418

318

View full text Add to dashboard Cite

show abstract

“…Tumor growth was measured three times weekly in two dimensions (length and width) with a vernier caliper. Tumor volume was calculated according to the formula: (width) 2 Â length Â 0.52 and reported as cm 3 . The median survival time (MST7SE) of tumor-bearing mice in each group was determined by life-table methods and by log-rank analysis.…”

Section: In Vitro Depletion Of T-cell Subsets and Nk Cellsmentioning

confidence: 99%

“…1,2 The antitumor immune responses following immunization with effective vaccines can be of sufficient magnitude to prolong the lives of experimental animals, and patients, providing a compelling rationale for the use of tumor vaccines in cancer therapy. 3,4 In breast cancer, TAA such as MUC-1, 5 HER-2/neu, 6 MAGE-1, 7 BAGE, 8 mammaglobin 9 and MENA 10 have been identified as potential targets of CTLs. It is likely that these are only several representations of an undefined, and possibly large number of TAA expressed by breast cancer cells.…”

mentioning

confidence: 99%

Immunity to breast cancer in mice immunized with fibroblasts transfected with a cDNA expression library derived from small numbers of breast cancer cells

Kim

Cohen

2005

Cancer Gene Ther

View full text Add to dashboard Cite

Immunotherapy of breast cancer at an early stage of the disease increases the likelihood of success. Here, in a mouse model, we report a new strategy that enables vaccines to be prepared from microgram amounts of tumor tissue. The vaccine is prepared by transfer of a cDNA expression library from relatively small numbers of breast cancer cells into a highly immunogenic cell line, where genes specifying TAA are expressed. As the transferred DNA is integrated and replicated as the recipient cells divide, the number of vaccine cells can be conveniently expanded for repeated immunizations. A cDNA expression library prepared from a breast cancer that arose spontaneously in a C3H/He mouse (H-2 k ) was transferred into a mouse fibroblast cell line derived from C3H/He mice. To augment their nonspecific immunogenic properties, the fibroblasts were genetically modified before DNA transfer to secrete IL-2 and to express allogeneic MHC class I H-2K b -determinants. C3H/He mice, highly susceptible to growth of the breast cancer cells, were immunized with the cDNA-transfected cells. Robust breast cancer-specific CD8 þ T-cell-mediated immunity was generated in the mice, raising the possibility that an analogous treatment strategy could be used to treat breast cancer patients at an early stage of the disease.

show abstract

“…Tumour targets have included the products of MAGE, HLA, tumour suppressor and other polymorphic genes (Robbins et al, 2002;Huang et al, 2004;Zhou et al, 2005). However, the process of cell generation requires the use of lymphocytes isolated from tumour biopsies and is labour intensive and impractical for routine clinical purposes.…”

mentioning

confidence: 99%

Generation of tumour-specific cytotoxic T-cell clones from histocompatibility leucocyte antigen-identical siblings of patients with melanoma

Gottlieb

Lionello

et al. 2006

Br J Cancer

View full text Add to dashboard Cite

Lymphodepletion and infusion of autologous expanded tumour-infiltrating lymphocytes is effective therapy for patients with malignant melanoma. Antitumour responses are likely to be mediated by HLA class I-and II-restricted immune responses directed at tumour antigens. We assessed whether the peripheral blood of normal HLA-matched siblings of patients with melanoma could be used to generate lymphocytes with antimelanoma activity for adoptive immunotherapy after allogeneic blood or marrow transplantation. Melanoma cell lines were derived from two donors and were used to stimulate the mononuclear cells of three HLAidentical siblings. CD4 þ clones dominated cultures. Of these, approximately half were directly cytotoxic towards recipient melanoma cells and secreted interferon-g in response to tumour stimulation. More than half of the noncytotoxic clones also secreted interferong after melanoma stimulation. No CD4 þ clones responded to stimulation with recipient haemopoietic cells. The majority of CD8 þ clones directly lysed recipient melanoma, but did not persist in long-term culture in vitro. No crossreactivity with recipient haemopoietic cells was observed. The antigenic target of one CD4 þ clone was determined to be an HLA-DR11-restricted MAGE-3 epitope. Antigenic targets of the remaining clones were not elucidated, but appeared to be restricted through a non-HLA-DR class II molecule. We conclude that the blood of allogeneic HLA-matched sibling donors contains melanoma-reactive lymphocyte precursors directed at tumour-associated antigens. Adoptive immunotherapy with unselected or ex vivo-stimulated donor lymphocytes after allogeneic stem cell transplantation has a rational basis for the treatment of malignant melanoma.

show abstract

Multiple HLA Class II-Restricted Melanocyte Differentiation Antigens Are Recognized by Tumor-Infiltrating Lymphocytes from a Patient with Melanoma

Cited by 70 publications

References 41 publications

The response of autologous T cells to a human melanoma is dominated by mutated neoantigens

The response of autologous T cells to a human melanoma is dominated by mutated neoantigens

Immunity to breast cancer in mice immunized with fibroblasts transfected with a cDNA expression library derived from small numbers of breast cancer cells

Generation of tumour-specific cytotoxic T-cell clones from histocompatibility leucocyte antigen-identical siblings of patients with melanoma

Contact Info

Product

Resources

About