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Expression of a "Self-"Antigen by Human Tumor Cells Enhances Tumor Antigen-specific CD4⁺ T-Cell Function

National Cancer Institute, NIH, Bethesda, Maryland 20892 [C. E. T., W. W. L., P. F. R., Y. F. L., R. L., P. H., S. A. R., N. P. R.], and ImClone Systems Incorporated, New York, New York 10014 [X. K.]

CD4⁺ T cells can recognize "self" tumor antigens, but the impact of tumor cell expression of self-antigens on CD4⁺ T-cell function in humans is unknown. Here, we identify a new epitope (ISPNSVFSQWRVVCDSLEDYD) derived from tyrosinase-related protein-1 (TRP-1) using a predictive algorithm and mice transgenic for a chimeric HLA-DRB1*0401 molecule. We then compared the functions of TRP-1-epitope-specific, CD4⁺ T-cell responses in normal healthy individuals to those found in patients with metastatic malignant melanoma. Surprisingly, we found that tumor-bearing patients had significantly higher levels of TRP-1-specific, CD4⁺ T-cell function than healthy volunteers as measured ex vivo. Thus, the net effect of "self" antigen expression by tumor cells was the enhancement of tumor antigen-specific CD4⁺ T-cell function, rather than immunosuppression. These findings indicate that antigens expressed by malignant melanoma cells can partially activate CD4⁺ T lymphocytes.

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