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

Julia Boshuizen, David W. Vredevoogd, Oscar Krijgsman, Maarten A. Ligtenberg, Stephanie Blankenstein, Beaunelle Bruijn, Dennie T. Frederick, Juliana C. N. Kenski, Mara Parren, Marieke Brüggemann, Max F. Madu, Elisa A. Rozeman, Ji-Ying Song, Hugo M. Horlings, Christian U. Blank, Alexander C. J. Akkooi, Keith T. Flaherty, Genevieve M. Boland and Daniel S. Peeper ()
Additional contact information
Julia Boshuizen: Oncode Institute, The Netherlands Cancer Institute
David W. Vredevoogd: Oncode Institute, The Netherlands Cancer Institute
Oscar Krijgsman: Oncode Institute, The Netherlands Cancer Institute
Maarten A. Ligtenberg: Oncode Institute, The Netherlands Cancer Institute
Stephanie Blankenstein: The Netherlands Cancer Institute
Beaunelle Bruijn: Oncode Institute, The Netherlands Cancer Institute
Dennie T. Frederick: Massachusetts General Hospital
Juliana C. N. Kenski: Oncode Institute, The Netherlands Cancer Institute
Mara Parren: Oncode Institute, The Netherlands Cancer Institute
Marieke Brüggemann: Oncode Institute, The Netherlands Cancer Institute
Max F. Madu: The Netherlands Cancer Institute
Elisa A. Rozeman: Oncode Institute, The Netherlands Cancer Institute
Ji-Ying Song: The Netherlands Cancer Institute
Hugo M. Horlings: The Netherlands Cancer Institute
Christian U. Blank: Oncode Institute, The Netherlands Cancer Institute
Alexander C. J. Akkooi: The Netherlands Cancer Institute
Keith T. Flaherty: Massachusetts General Hospital
Genevieve M. Boland: Massachusetts General Hospital
Daniel S. Peeper: Oncode Institute, The Netherlands Cancer Institute

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17739-8

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