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A mutated HLA-A2 molecule recognized by autologous cytotoxic T lymphocytes on a human renal cell carcinoma
D Brändle1, F Brasseur, P Weynants
1Ludwig Institute for Cancer Research, Université Catholique de Louvain, Brussels, Belgium.
Abstract:
Many human tumor cells have been shown to express antigens that are recognized by autologous cytotoxic T lymphocytes (CTL) and the molecular nature of a number of melanoma antigens has been defined recently. Here we describe the characterization of an antigen recognized on a renal cell carcinoma by autologous CTL clones. This antigen is encoded by the HLA-A2 gene present in the tumor cells. The sequence of this gene differs from the HLA-A2 sequence found in autologous peripheral blood lymphocytes by a point mutation that results in an arginine to isoleucine exchange at residue 170, which is located on the alpha-helix of the alpha 2 domain. Transfection experiments with the normal and mutated HLA-A2 cDNA demonstrated that this amino acid replacement was responsible for the recognition of the HLA-A2 molecule expressed on the tumor cells. The mutant HLA-A2 gene was also detected in the original tumor tissue from the patient, excluding the possibility that the mutation had appeared in vitro. Thus, HLA class I molecules carrying a tumor-specific mutation can be involved in the recognition of tumor cells by autologous CTL.
Insights
Tumor cells can express mutated HLA-A2 antigens recognized by cytotoxic T lymphocytes (CTL). A specific point mutation in the HLA-A2 gene on renal cell carcinoma cells triggers this immune response.
Area of Science:
- Immunology
- Oncology
- Genetics
Background:
- Human tumor cells express antigens recognized by autologous cytotoxic T lymphocytes (CTL).
- The molecular identity of several melanoma antigens has been recently elucidated.
- Antigen recognition by CTL is crucial for anti-tumor immunity.
Purpose of the Study:
- To characterize a tumor-specific antigen recognized by autologous CTL clones in renal cell carcinoma.
- To identify the genetic basis of the antigen and its role in CTL recognition.
- To investigate the involvement of mutated HLA class I molecules in tumor cell recognition.
Main Methods:
- Isolation and characterization of autologous CTL clones recognizing renal cell carcinoma.
- Sequencing of the HLA-A2 gene in tumor cells and autologous peripheral blood lymphocytes.
- Transfection experiments using normal and mutated HLA-A2 cDNA.
- Detection of the mutant HLA-A2 gene in tumor tissue.
Main Results:
- An antigen recognized by autologous CTL clones was identified on renal cell carcinoma.
- This antigen is encoded by a mutated HLA-A2 gene present in tumor cells.
- A point mutation (arginine to isoleucine at residue 170) in the HLA-A2 gene was responsible for tumor cell recognition by CTL.
- The mutation was confirmed to be tumor-specific and not an in vitro artifact.
Conclusions:
- Tumor-specific mutations in HLA class I molecules can lead to the generation of antigens recognized by autologous CTL.
- Mutated HLA-A2 molecules can serve as targets for CTL-mediated anti-tumor immunity.
- This finding highlights the potential of targeting tumor-specific HLA mutations for cancer immunotherapy.