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

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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.

Original languageEnglish
JournalCancer Research
Volume77
Issue number17
Pages (from-to)4562-4566
Number of pages5
ISSN0008-5472
DOIs
Publication statusPublished - 1 Sep 2017

    Research areas

  • Antigen Presentation, Antigens, Neoplasm, Histocompatibility Antigens Class I, Humans, Immunotherapy, Interferon-gamma, Melanoma, Neoplasm Metastasis, Neoplasm Recurrence, Local, T-Lymphocytes, Cytotoxic, Tumor Escape, Journal Article

ID: 52211010