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
  • 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. [email protected].
  • # 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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