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UV-induced N-ras mutations are T-cell targets in human melanoma
A van Elsas1, C Scheibenbogen, C van der Minne
1Department of Clinical Oncology, University Hospital Leiden, The Netherlands.
Abstract:
Human cutaneous melanoma is heterogeneous with respect to the genetic aberrations involved and the genes altered are potential targets for the immune system. The incidence of cutaneous melanoma is known to be linked to UV peak exposure, and the N-ras oncogene is clearly one of the genes involved in the UV carcinogenesis in melanoma. It is mutated in a significant proportion of melanomas and therefore may serve as a target for T cells. Here, we report that an human leukocyte antigen-A2 binding peptide CLLDILDTAGL, encompassing the frequently found 61-Leu mutation in N-ras, induces cytotoxic T lymphocytes from healthy donor blood that lyse 61-Leu N-ras transfected melanoma cells. Furthermore, we have found an association between the presence of N-ras mutations and clinical response to immunotherapy with interleukin-2 plus interferon in a group of stage IV melanoma patients. Although the overall survival of these patients was not affected by the N-ras status of their melanomas, these studies suggest that mutated N-ras may provide a target for cytotoxic T lymphocytes in melanoma patients.
Insights
Mutated N-ras oncogenes in melanoma can be targeted by T cells. A specific peptide induced T cells to kill melanoma cells with the N-ras mutation, suggesting a new immunotherapy approach.
Area of Science:
- Oncology
- Immunology
- Dermatology
Background:
- Human cutaneous melanoma exhibits genetic heterogeneity, with altered genes presenting potential immune targets.
- Ultraviolet (UV) radiation exposure is linked to melanoma incidence, and N-ras oncogene mutations are implicated in UV carcinogenesis.
- The N-ras oncogene is frequently mutated in melanomas, making it a potential target for T cell-mediated immunotherapy.
Purpose of the Study:
- To investigate the potential of targeting N-ras mutations in melanoma using immunotherapy.
- To determine if a specific peptide encompassing the N-ras 61-Leu mutation can induce cytotoxic T lymphocytes (CTLs) against melanoma cells.
- To explore the association between N-ras mutations and clinical response to immunotherapy in advanced melanoma patients.
Main Methods:
- Development of a human leukocyte antigen-A2 (HLA-A2) binding peptide (CLLDILDTAGL) containing the N-ras 61-Leu mutation.
- Induction of CTLs from healthy donor blood using the N-ras peptide.
- Assessment of CTL-mediated lysis of melanoma cells transfected with the 61-Leu N-ras mutation.
- Analysis of N-ras mutation status in stage IV melanoma patients and correlation with clinical response to interleukin-2 (IL-2) plus interferon (IFN) immunotherapy.
Main Results:
- The synthesized peptide successfully induced N-ras-specific CTLs from healthy donors.
- These induced CTLs demonstrated the ability to lyse melanoma cells harboring the 61-Leu N-ras mutation.
- A correlation was observed between the presence of N-ras mutations and clinical response to IL-2 plus IFN immunotherapy in stage IV melanoma patients.
- No significant impact of N-ras mutation status on overall survival was found in this patient cohort.
Conclusions:
- Mutated N-ras represents a viable target for T cell-based immunotherapy in melanoma.
- The N-ras 61-Leu mutation-specific peptide can elicit an anti-melanoma immune response.
- N-ras mutations may serve as a predictive biomarker for immunotherapy response in certain melanoma patient groups.