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Fine analysis of spontaneous MAGE-C1/CT7-specific immunity in melanoma patients
Natko Nuber1, Alessandra Curioni-Fontecedro, Claudia Matter
1Department of Oncology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
Abstract:
Cancer/testis (CT) antigens represent prime candidates for immunotherapy in cancer patients, because their expression is restricted to cancer cells and germ cells of the testis. MAGE-C1/CT7 is a CT antigen that is highly expressed in several types of cancers. Spontaneous occurrence of CT7-specific antibodies was previously detected by SEREX screen in a melanoma patient. However, naturally occurring CT7-specific T-cell responses have thus far not been detected. Peripheral blood mononuclear cells (PBMCs) from 26 metastatic melanoma patients expressing CT7 in their tumor lesions (CT7(+)) were analyzed for CT7-specific T-cell responses using overlapping peptides. CT7-specific CD4(+) T-cell responses were detected in three patients (11.5%). These CT7-specific CD4(+) T-cell responses were detectable in melanoma patients' PBMCs exclusively from preexisting CD45RA(-) memory CD4(+) T-cell pool. Additional CT7-specific memory CD4(+) T-cell responses were detected in CT7(+) melanoma patients after depletion of CD4(+)CD25high Treg cells showing that Treg cells impact on CT7-specific CD4(+) T cells in melanoma patients. CT7-specific CD4(+) T-cell clones were generated and used to define minimal epitopes, restriction elements, and confirm the recognition of naturally processed antigen. Surprisingly, these clones were able to secrete perforin and exert cytotoxicity. This study shows that CT7 can induce specific cellular immunity in melanoma patients. Based on these findings, CT7 will be further explored as a potential vaccine for melanoma immunotherapy.
Insights
Cancer/testis antigen CT7 elicits a CD4(+) T-cell response in melanoma patients, suggesting its potential as a vaccine for cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Cancer/testis (CT) antigens, like MAGE-C1/CT7, are promising targets for cancer immunotherapy due to their restricted expression in cancer and germ cells.
- While CT7-specific antibodies have been observed, naturally occurring CT7-specific T-cell responses in cancer patients remained undetected.
Purpose of the Study:
- To investigate the presence of CT7-specific T-cell responses in patients with metastatic melanoma.
- To characterize the nature of these T-cell responses and their potential for therapeutic application.
Main Methods:
- Analysis of peripheral blood mononuclear cells (PBMCs) from 26 metastatic melanoma patients (CT7(+)) using overlapping peptides to detect CT7-specific T-cell responses.
- Characterization of T-cell subsets involved, including memory CD4(+) T cells and regulatory T cells (Tregs).
- Generation of CT7-specific CD4(+) T-cell clones to define epitopes and assess cytotoxic potential.
Main Results:
- CT7-specific CD4(+) T-cell responses were detected in 11.5% of melanoma patients.
- These responses originated from the memory CD4(+) T-cell pool and were influenced by regulatory T cells (Tregs).
- Generated CT7-specific T-cell clones demonstrated cytotoxic activity, secreting perforin.
Conclusions:
- CT7 can induce a specific cellular immune response in melanoma patients.
- CT7-specific CD4(+) T cells, capable of cytotoxicity, are present in melanoma patients.
- CT7 holds potential as a target for developing a melanoma immunotherapy vaccine.
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