Immunity against cancer: lessons learned from melanoma

Houghton, Alan N.; Gold, Jason S.; Blachère, Nathalie E.

doi:10.1016/s0952-7915(00)00195-3

Cited by 181 publications

(132 citation statements)

References 50 publications

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“…Although several lines of evidence point to the clinical relevance of host antitumor T cell responses, pathways leading to antitumor immunity or causing the immune system's failure to eliminate transformed cells are by far not understood (15); this may explain why therapeutic vaccination studies performed during the last decade led only to a limited and unsatisfying success rate. Regressions of metastases after therapeutic vaccination were observed only in a minority of patients (16), and there was only weak evidence that in vivo expansion of T cells directed against vaccine antigens correlated with tumor regression (17,18).…”

Section: Discussionmentioning

confidence: 99%

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.

413

318

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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

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Section: Discussionmentioning

confidence: 99%

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.

413

318

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“…Given the fact that CD4 ϩ effector T cells are not only required for the priming and maintenance of CD8 ϩ T cells, thus enhancing the immune response against cancer (4,5), but also essential for enhancing the expansion of memory CD8 ϩ T cells (6 -8), it is of particular interest to know whether MHC class II-restricted peptides preferentially activate CD4 ϩ Treg or effector cells. For example, a SEREX-defined autoantigen, Dna J-like 2, activates CD4 ϩ CD25 ϩ Treg cells and suppress antitumor immune response in mice (48).…”

Section: Discussionmentioning

confidence: 99%

“…Clinical trials using cancer peptides or peptide-pulsed dendritic cells (DCs) 3 have produced some evidence of Ag-specific immunological responses in most patients as well as clinical responses in a small percentage of the treated patients, but overall, the immune responses in most patients have been weak and transient (1)(2)(3). Among many factors that may contribute to this failure, the lack of CD4 ϩ Th (effector) cell response is thought to be critical, because such T cells are required for the priming and maintenance of CD8 ϩ T cells, thus enhancing the immune response against cancer (4,5). Recent studies support the notion that CD4 ϩ T cells enhance the expansion of memory CD8 ϩ T cells (6 -8).…”

Section: Olecular Identification Of Tumor Ags Has Provided Newmentioning

confidence: 99%

Recognition of a New ARTC1 Peptide Ligand Uniquely Expressed in Tumor Cells by Antigen-Specific CD4+ Regulatory T Cells

Wang

Peng

Guo

et al. 2005

The Journal of Immunology

146

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CD4+ regulatory T (Treg) cells play an important role in the maintenance of immunological self-tolerance by suppressing immune responses against autoimmune diseases and cancer. Yet very little is known about the natural antigenic ligands that preferentially activate CD4+ Treg cells. Here we report the establishment of tumor-specific CD4+ Treg cell clones from tumor-infiltrating lymphocytes (TILs) of cancer patients, and the identification of an Ag recognized by Treg cells (ARTC1) gene encoding a peptide ligand recognized by tumor-specific TIL164 CD4+ Treg cells. The mutations in a gene encoding an ARTC1 in 164mel tumor cells resulted in the translation of a gene product containing the peptide ligand recognized by CD4+ Treg cells. ARTC1 peptide-activated CD4+ Treg cells suppress the physiological function (proliferation and IL-2 secretion) of melanoma-reactive T cells. Furthermore, 164mel tumor cells, but not tumor lysates pulsed on B cells, were capable of activating TIL164 CD4+ Treg cells. These results suggest that tumor cells may uniquely present an array of peptide ligands that preferentially recruit and activate CD4+ Treg cells in sites where tumor-specific self-peptide is expressed, leading to the induction of local and tumor-specific immune suppression.

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“…Immunity against a major class of self Ags, the differentiation Ags, can be induced by xenogeneic immunization, which is vaccination of a host from one species with DNA encoding an orthologous gene from another species (1)(2)(3)(4). Differentiation Ags are shared between cancer cells and their normal cell counterparts (5). The strategy of xenogeneic immunization has been successful, whereas immunization with the syngeneic differentiation Ag failed to induce immunity.…”

mentioning

confidence: 99%

A Single Heteroclitic Epitope Determines Cancer Immunity After Xenogeneic DNA Immunization Against a Tumor Differentiation Antigen

Gold

Ferrone

Guevara-Patiño

et al. 2003

The Journal of Immunology

104

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Successful active immunization against cancer requires induction of immunity against self or mutated self Ags. However, immunization against self Ags is difficult. Xenogeneic immunization with orthologous Ags induces cancer immunity. The present study evaluated the basis for immunity induced by active immunization against a melanoma differentiation Ag, gp100. Tumor rejection of melanoma was assessed after immunization with human gp100 (hgp100) DNA compared with mouse gp100 (mgp100). C57BL/6 mice immunized with xenogeneic full-length hgp100 DNA were protected against syngeneic melanoma challenge. In contrast, mice immunized with hgp100 DNA and given i.p. tolerizing doses of the hgp100 Db-restricted peptide, hgp10025–33, were incapable of rejecting tumors. Furthermore, mice immunized with DNA constructs of hgp100 in which the hgp10025–27 epitope was substituted with the weaker Db-binding epitope from mgp100 (mgp10025–27) or a mutated epitope unable to bind Db did not reject B16 melanoma. Mice immunized with a minigene construct of hgp10025–33 rejected B16 melanoma, whereas mice immunized with the mgp10025–33 minigene did not develop protective tumor immunity. In this model of xenogeneic DNA immunization, the presence of an hgp100 heteroclitic epitope with a higher affinity for MHC created by three amino acid (25 to 27) substitutions at predicted minor anchor residues was necessary and sufficient to induce protective tumor immunity in H-2b mice with melanoma.

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Immunity against cancer: lessons learned from melanoma

Cited by 181 publications

References 50 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

Recognition of a New ARTC1 Peptide Ligand Uniquely Expressed in Tumor Cells by Antigen-Specific CD4+ Regulatory T Cells

A Single Heteroclitic Epitope Determines Cancer Immunity After Xenogeneic DNA Immunization Against a Tumor Differentiation Antigen

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