2. Academic Validation
  3. 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.
PMID: 32770055 DOI: 10.1038/s41467-020-17739-8
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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