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

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

SUBMITTER: Boshuizen J 

PROVIDER: S-EPMC7414147 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature