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.
Author Info: (1) Center for Cancer Immune Therapy and Department of Oncology, Herlev Hospital, University of Copenhagen doniamarco@gmail.com. (2) Oncology, Lund University. (3) Netherlands Canc
Author Info: (1) Center for Cancer Immune Therapy and Department of Oncology, Herlev Hospital, University of Copenhagen doniamarco@gmail.com. (2) Oncology, Lund University. (3) Netherlands Cancer Institute. (4) (5) Department of Surgery, Sahlgrenska Cancer Center, University of Gothenburg. (6) Center for Cancer ImmuneTherapy and Department of Haematology and Oncology, Herlev Hospital, University of Copenhagen. (7) Department of Hematology, 54P4, Herlev Hospital. (8) Center for Cancer Immune Therapy, Herlev Hospital, Copenhagen University. (9) Center for Cancer Immune Therapy and Department of Oncology, Herlev Hospital, University of Copenhagen. (10) Institute of Medical Immunology, Martin Luther University Halle-Wittenberg. (11) Department of Biomedical Sciences, University of Catania. (12) Bio-medical Sciences, University of Catania. (13) Department of Biomedical Sciences, University of Catania. (14) Clinical Sciences, Lund University Hospital. (15) Division for Immunology and Vaccinology, Technical University of Denmark. (16) Oncology, Aarhus University Hospital. (17) Center for Cancer Immune Therapy, 54P4, Herlev Hospital. (18) Dept of Hematology, Center for Cancer Immune Therapy, Copenhagen. (19) Sahlgrenska Cancer Center, University of Gothenburg. (20) Immunology, Netherlands Cancer Institute. (21) Institute of Medical Immunology, Martin Luther University Halle-Wittenberg. (22) Division of Oncology and Pathology, Lund University. (23) Center for Cancer Immune Therapy, Copenhagen University Hospital, Herlev.
