1. Academic Validation
  2. Reversal of pre-existing NGFR-driven tumor and immune therapy resistance

Reversal of pre-existing NGFR-driven tumor and immune therapy resistance

  • Nat Commun. 2020 Aug 7;11(1):3946. doi: 10.1038/s41467-020-17739-8.
Julia Boshuizen 1 David W Vredevoogd  # 1 Oscar Krijgsman  # 1 Maarten A Ligtenberg 1 Stephanie Blankenstein 2 Beaunelle de Bruijn 1 Dennie T Frederick 3 Juliana C N Kenski 1 Mara Parren 1 Marieke Brüggemann 1 Max F Madu 2 Elisa A Rozeman 1 Ji-Ying Song 4 Hugo M Horlings 5 Christian U Blank 1 Alexander C J van Akkooi 2 Keith T Flaherty 6 Genevieve M Boland 3 Daniel S Peeper 7
Affiliations

Affiliations

  • 1 Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 2 Division of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 3 Department of Surgical Oncology, Massachusetts General Hospital, Boston, MA, USA.
  • 4 Division of Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 5 Division of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 6 Department of Medical Oncology, Massachusetts General Hospital, Boston, MA, USA.
  • 7 Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. d.peeper@nki.nl.
  • # Contributed equally.
Abstract

Melanomas can switch to a dedifferentiated cell state upon exposure to cytotoxic T cells. However, it is unclear whether such tumor cells pre-exist in patients and whether they can be resensitized to immunotherapy. Here, we chronically expose (patient-derived) melanoma cell lines to differentiation antigen-specific cytotoxic T cells and observe strong enrichment of a pre-existing NGFRhi population. These fractions are refractory also to T cells recognizing non-differentiation antigens, as well as to BRaf + MEK inhibitors. NGFRhi cells induce the neurotrophic factor BDNF, which contributes to T cell resistance, as does NGFR. In melanoma patients, a tumor-intrinsic NGFR signature predicts anti-PD-1 therapy resistance, and NGFRhi tumor fractions are associated with immune exclusion. Lastly, pharmacologic NGFR inhibition restores tumor sensitivity to T cell attack in vitro and in melanoma xenografts. These findings demonstrate the existence of a stable and pre-existing NGFRhi multitherapy-refractory melanoma subpopulation, which ought to be eliminated to revert intrinsic resistance to immunotherapeutic intervention.

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