An Endoplasmic Reticulum Stress-specific Caspase Cascade in Apoptosis CYTOCHROME c-INDEPENDENT ACTIVATION OF CASPASE-9 BY CASPASE-12

Cancer/testis (CT) antigens are immunogenic in cancer patients, exhibit highly tissue-restricted expression, and are considered promising target molecules for cancer vaccines. To date, 44 CT gene families have been identified and their expression studied in numerous cancer types. For example, bladder cancer, non-small cell lung cancer, and melanoma are high CT gene expressors, with 11/20 (55%), 17/33 (51%) and 17/32 (53%) of the CT transcripts examined by RT-PCR detected in 20% or more of the specimens examined, respectively. Breast and prostate cancer can be considered moderate CT gene expressors, with 12/32 (37%) and 6/20 (30%) CT transcripts having an expression frequency >20%, respectively, while renal and colon cancer are low CT gene expressors, with only 3/33 (9%) and 4/25 (16%) CT transcripts having an expression frequency >20%, respectively. In normal tissues, standardized RT-PCR experiments showed that 19/43 CT genes were testis-restricted, 10/43 CT genes were tissue-restricted (mRNA detected in 2 or fewer non-gametogenic tissues), 9/43 CT genes were differentially expressed (mRNA detected in 3-6 non-gametogenic tissues), and 5/43 CT genes were ubiquitously expressed. With the exception of testis-restricted CT transcripts, all remaining CT transcripts were expressed in normal pancreas. In terms of immunogenicity, 14/29 testis/tissue-restricted CT gene families have been shown to induce a cellular and/or humoral immune response in humans. In view of the expanding list of CT genes, a CT gene database was created to standardize CT nomenclature and accumulate relevant data regarding their expression profiles, immunogenicity, function (where known), gene structure and location, and orthologous groups.

https://cancerimmunolres.aacrjournals.org/content/canimmarch/4/1/1.full.pdf

The cancer/testis genes: review, standardization, and commentary.

The Melan-A/MART-1 gene, which is expressed by normal melanocytes as well as by most fresh melanoma samples and melanoma cell lines, codes for Ags recognized by tumor-reactive CTL. HLA-A*0201-restricted Melan-A-specific CTL recognize primarily the Melan-A27-35 (AAGIGILTV) and the Melan-A26-35 (EAAGIGILTV) peptides. The sequences of these two peptides are not necessarily optimal as far as binding to HLA-A*0201 is concerned, since both lack one of the dominant anchor amino acid residues (leucine or methionine) at position 2. In this study we introduced single amino acid substitutions in either one of the two natural peptide sequences with the aim of improving peptide binding to HLA-A*0201 and/or recognition by specific CTL. Surprisingly, analogues of the Melan-A27-35 peptide, which bound more efficiently than the natural nonapeptide to HLA-A*0201, were poorly recognized by tumor-reactive CTL. In contrast, among the Melan-A26-35 peptide analogues tested, the peptide ELAGIGILTV was not only able to display stable binding to HLA-A2.1 but was also recognized more efficiently than the natural peptide by two short-term cultured tumor-infiltrated lymph node cell cultures as well as by five of five tumor-reactive CTL clones. Moreover, in vitro generation of tumor-reactive CTL by stimulation of PBMC from HLA-A*0201 melanoma patients with this particular peptide analogue was much more efficient than that observed with either one of the two natural peptides. These results suggest that the Melan-A26-35 peptide analogue ELAGIGILTV may be more immunogenic than the natural peptides in HLA-A*0201 melanoma patients and should thus be considered as a candidate for future peptide-based vaccine trials.

Enhanced Generation of Specific Tumor-Reactive CTL In Vitro by Selected Melan-A/MART-1 Immunodominant Peptide Analogues

In this study we used TEPITOPE, a new epitope prediction software, to identify sequence segments on the MAGE-3 protein with promiscuous binding to histocompatibility leukocyte antigen (HLA)-DR molecules. Synthetic peptides corresponding to the identified sequences were synthesized and used to propagate CD4+ T cells from the blood of a healthy donor. CD4+ T cells strongly recognized MAGE-3281–295 and, to a lesser extent, MAGE-3141–155 and MAGE-3146–160. Moreover, CD4+ T cells proliferated in the presence of recombinant MAGE-3 after processing and presentation by autologous antigen presenting cells, demonstrating that the MAGE-3 epitopes recognized are naturally processed. CD4+ T cells, mostly of the T helper 1 type, showed specific lytic activity against HLA-DR11/MAGE-3–positive melanoma cells. Cold target inhibition experiments demonstrated indeed that the CD4+ T cells recognized MAGE-3281–295 in association with HLA-DR11 on melanoma cells. This is the first evidence that a tumor-specific shared antigen forms CD4+ T cell epitopes. Furthermore, we validated the use of algorithms for the prediction of promiscuous CD4+ T cell epitopes, thus opening the possibility of wide application to other tumor-associated antigens. These results have direct implications for cancer immunotherapy in the design of peptide-based vaccines with tumor-specific CD4+ T cell epitopes.

https://rupress.org/jem/article-pdf/189/5/871/1120273/98-1989.pdf

Melanoma Cells Present a MAGE-3 Epitope to CD4+ Cytotoxic T Cells in Association with Histocompatibility Leukocyte Antigen DR11

The Multi-epitope Approach for Immunotherapy for Cancer: Identification of Several CTL Epitopes from Various Tumor-Associated Antigens Expressed on Solid Epithelial Tumors ☆

The human MAGE-3 gene encodes a melanoma antigenic epitope recognized by specific cytotoxic T lymphocytes, but its gene product has not been identified thus far. We produced a recombinant MAGE-3 gene product by expression cloning of the entire reading frame in the context of a fusion protein characterized by a 10-histidine tail, allowing purification by metal chelation on a nickel Sepharose column. The semipurified product was used to generate MAGE-3-specific monoclonal antibodies. One reagent could identify by immunoblotting the native MAGE-3 gene product as a M r 48,000 protein in lysates of cell lines showing evidence of MAGE-3 gene expression. No apparent cross-reactivity with recombinant or native MAGE-1 gene product was observed. Immunohistochemistry shows that, closely resembling the MAGE-1 gene product, MAGE-3 is a cytoplasmic protein.

/pdf/identification-and-intracellular-location-of-mage-3-gene-4bllox4420.pdf

Identification and Intracellular Location of MAGE-3 Gene Product

Peptide specificity of cultured tumor-infiltrating lymphocytes (TIL) was systematically investigated in a group of HLA-A2.1+ metastatic melanoma patients consecutively referred to our department for surgical treatment. Seven samples from 6 patients were studied. All surgical specimens showed evidence of gp 100, MART-1/Melan-A and Tyrosinase gene expression as detectable by reverse PCR (rPCR). Cultured TIL from 2 patients displayed cytotoxic activity against autologous or HLA-matched EBV-transformed cells previously pulsed with MART-1/Melan-A27-35 peptide. In contrast, no CTL activity against gp100(280-288) or tyrosinase1-9 peptides could be observed. TIL were then repeatedly stimulated in vitro with the same peptides. After 6 restimulation courses at weekly intervals, specific recognition of gp100(280-288) and MART-1/Melan-A peptides was detectable in 3 and 5 TIL populations, respectively. In one case Tyrosinase1-9-specific CTL could be demonstrated. Two TIL populations from metastases resected from a melanoma patient at 6 months' distance showed a different peptide specificity pattern, and no specific CTL could be generated from simultaneously sampled peripheral blood mononuclear cells (PBMC). All peptide-specific CTL populations also displayed significant cytotoxic activity against HLA-A2.1 matched melanoma cell lines expressing the antigens under investigation. Our data indicate that CTL specific for MART-Melan-A27-35, gp100(280-288) or Tyrosinase1-9 peptides could be expanded with varying frequency from TIL derived from 4 out of 6 HLA-A2.1+ patients whose tumors expressed the genes encoding these tumor-associated antigens (TAA).

Peptide‐specific ctl in tumor‐infiltrating lymphocytes from metastatic melanomas expressing mart‐1/melan‐a, gp100 and tyrosinase genes: A study in an unselected group of hla‐a2.1‐positive patients

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Identification and Intracellular Location of MAGE-3 Gene Product

Peptide‐specific ctl in tumor‐infiltrating lymphocytes from metastatic melanomas expressing mart‐1/melan‐a, gp100 and tyrosinase genes: A study in an unselected group of hla‐a2.1‐positive patients