The Unexpected Benefit of TCR Cross-Reactivity in Cancer Immunotherapy

Abstract The ability of T-cell receptors (TCR) to recognize tumor-associated antigens (TAA) is a key driver of adoptive transfer of tumor-infiltrating lymphocyte (TIL) T cells, which can be a highly effective cancer immunotherapy. While it is common knowledge that TCRs are cross-reactive and can bind multiple different peptide antigens, this is typically considered an unattractive feature and limitation for TCR-based therapies. In a recent publication in Cell, Dolton and colleagues discover that certain TCRs, isolated from TILs used for successful treatment of melanoma, possess beneficial cross-reactivity by recognizing multiple TAA. Moreover, they elucidate the cumulative value of TCR cross-reactivity on cancer cell eradication and its prospective advantages for targeted cancer immunotherapies.