Reversal of pre-existing NGFR-driven tumor and immune therapy resistance
Julia Boshuizen, David W. Vredevoogd, Oscar Krijgsman, Maarten A. Ligtenberg, Stéphanie A. Blankenstein, Beaunelle de 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. van Akkooi, Keith T. Flaherty, Genevieve M. Boland, Daniel S. Peeper
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 NGFR hi population. These fractions are refractory also to T cells recognizing non-differentiation antigens, as well as to BRAF + MEK inhibitors. NGFR hi 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 NGFR hi 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 NGFR hi multitherapy-refractory melanoma subpopulation, which ought to be eliminated to revert intrinsic resistance to immunotherapeutic intervention.