Acquired immune resistance follows complete tumor regression without loss of target antigens or IFNγ signaling

Research output: Contribution to journalArticle

Abstract

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 CD8þ 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.

Details

Authors
  • Marco Donia
  • Marit M van Buuren
  • Pia Kvistborg
  • Mattias F. Lindberg
  • Rikke Dorothea Andersen
  • Manja Idorn
  • Shamaila Munir Ahmad
  • Eva Ellebæk
  • Anja Mueller
  • Paolo Fagone
  • Ferdinando Nicoletti
  • Massimo Libra
  • Sine Reker Hadrup
  • Henrik Schmidt
  • Mads Hald Andersen
  • Per Thor Straten
  • Jonas Nilsson
  • Ton N Schumacher
  • Barbara Seliger
  • Inge Marie Svane
Organisations
External organisations
  • Copenhagen University Hospital
  • University of Copenhagen
  • Netherlands Cancer Institute
  • Neon Therapeutics
  • University of Gothenburg
  • Martin-Luther-Universität Halle-Wittenberg
  • University of Catania
  • Technical University of Denmark
  • Aarhus University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Pages (from-to)4562-4566
Number of pages5
JournalCancer Research
Volume77
Issue number17
Publication statusPublished - 2017 Sep 1
Publication categoryResearch
Peer-reviewedYes