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A breast and melanoma-shared tumor antigen: T cell responses to antigenic peptides translated from different open
R F Wang1, S L Johnston, G Zeng
1Surgery Branch, National Cancer Institute, Bethesda, MD 20892, USA. rongfu@pop.nci.nih.gov
Abstract:
Infusion of TIL586 along with IL-2 into the autologous patient with metastatic melanoma resulted in the objective regression of tumor. Here, we report that screening a cDNA library from the 586mel cell line using CTL clones derived from TIL586 resulted in the isolation of a gene, CAG-3 (cancer Ag gene 3). Sequence analysis revealed that CAG-3 encodes an open reading frame identical to NY-ESO-1, which was recently reported to be recognized by autologous serum from a patient with esophageal cancer. Thus, NY-ESO-1 appears to be an immune target for both Ab- and T cell-mediated responses. Significantly, NY-ESO-1-specific CTL clones were capable of recognizing two HLA-A31-positive fresh and cultured breast tumors. To our knowledge, this represents the first direct demonstration that tumor-specific CTL clones can recognize both breast and melanoma tumor cells. A 10-mer antigenic peptide ESO10-53 (ASGPGGGAPR) was identified from the normal open reading frame of NY-ESO-1 based on its ability to sensitize HLA-A31-positive target cells for cytokine release and specific lysis. Interestingly, two additional CTL clones that were sensitized with NY-ESO-1 recognized two overlapping antigenic peptides derived from an alternative open reading frame of the same gene. These findings indicate that CTLs simultaneously responded to two different gene products translated from the normal and alternative reading frames of the same gene. Understanding of this mechanism by which the alternative reading frame is translated may have important implications in tumor immunology.
Insights
Tumor-infiltrating lymphocytes (TILs) targeting the cancer antigen gene 3 (CAG-3), also known as NY-ESO-1, demonstrated effectiveness against melanoma and breast tumors. This study identified NY-ESO-1 as a dual target for antibody and T-cell responses.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Metastatic melanoma treatment with tumor-infiltrating lymphocytes (TILs) and interleukin-2 (IL-2) showed objective tumor regression.
- Screening of a cDNA library from the 586mel cell line using TIL586-derived CTL clones led to the identification of a novel gene.
Purpose of the Study:
- To identify the gene targeted by TIL586 and investigate its role in anti-tumor immunity.
- To determine if the identified gene product is recognized by T-cells in other cancer types.
Main Methods:
- cDNA library screening using CTL clones.
- Sequence analysis of the isolated gene.
- Testing of NY-ESO-1 specific CTL clones against breast and melanoma tumor cells.
- Identification of antigenic peptides from NY-ESO-1.
Main Results:
- The isolated gene, CAG-3, was found to be identical to NY-ESO-1, a known immune target.
- NY-ESO-1 specific CTL clones recognized both HLA-A31-positive breast and melanoma tumor cells.
- A 10-mer antigenic peptide (ESO10-53) was identified from the normal reading frame of NY-ESO-1.
- CTLs recognized peptides from both normal and alternative reading frames of NY-ESO-1.
Conclusions:
- NY-ESO-1 is recognized by both antibody and T-cell mediated responses, serving as a dual immune target.
- This study provides the first direct evidence of tumor-specific CTLs recognizing both breast and melanoma tumor cells.
- The identification of NY-ESO-1 peptides from alternative reading frames suggests a novel mechanism of tumor antigen presentation with potential implications for cancer immunotherapy.