Studying the case of a patient who relapsed after a complete radiologic response following TIL therapy, Donia et al. observed evidence for a strong, but ineffective T cell response in the relapsed tumor and multiple defects in antigen-processing machinery (APM) in a cell line from the relapsed tumor, suggesting APM deficiency may be an important mechanism of adaptive resistance.
Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease recurrence following an initial, unequivocal radiologic complete regression after T cell-based immunotherapy. Functional cytotoxic T cell responses, including responses to one mutant neo-antigen, were amplified effectively with therapy and generated durable immunological memory. However, these immune responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I antigen processing and presentation machinery (APM) in resistant cancer cells, but not antigen loss or impaired IFN-gamma signaling, led to impaired recognition by tumor-specific CD8+ T cells. Our results suggest that future immunotherapy combinations should take into account targeting cancer cells with intact and impaired MHC class I-related APM. Loss of target antigens or impaired IFN-gamma signaling does not appear to be mandatory for tumor relapse after a complete radiologic regression. Personalized studies to uncover mechanisms leading to disease recurrence within each individual patient are warranted.