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Cancer Res. 2017 Sep 1;77(17):4562-4566. doi: 10.1158/0008-5472.CAN-16-3172. Epub 2017 Jun 27.

Acquired Immune Resistance Follows Complete Tumor Regression without Loss of Target Antigens or IFNγ Signaling.

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Department of Hematology, Center for Cancer Immune Therapy, Copenhagen University Hospital, Herlev, Denmark.
Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.
Division of Oncology and Pathology, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Sweden.
Division of Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
Department of Hematology, Center for Cancer Immune Therapy, Copenhagen University Hospital, Herlev, Denmark.
Institute for Medical Immunology, Martin Luther University, Halle-Wittenberg, Germany.
Department of Bio-medical Sciences, University of Catania, Catania, Italy.
Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.


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 neoantigen, were amplified effectively with therapy and generated durable immunologic 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 IFNγ 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 IFNγ 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. Cancer Res; 77(17); 4562-6. ©2017 AACR.

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