Tumor-specific neo-antigens that arise as a consequence of mutations^, are thought to be important for the therapeutic efficacy of cancer immunotherapies^,,. Accumulating evidence suggests that neo-antigens may be commonly recognized by intratumoral CD8⁺ T cells^,,,,, but it is unclear whether neo-antigen–specific CD4⁺ T cells also frequently reside within human tumors. In view of the accepted role of tumor-specific CD4⁺ T-cell responses in tumor control^,,, we addressed whether neo-antigen–specific CD4⁺ T-cell reactivity is a common property in human melanoma.