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

Julia Boshuizen1, David W Vredevoogd1, Oscar Krijgsman1

  • 1Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Nature Communications
|August 10, 2020
PubMed

Insights

A pre-existing melanoma cell subpopulation expressing high levels of nerve growth factor receptor (NGFR) is resistant to immunotherapy and BRAF/MEK inhibitors. Inhibiting NGFR may restore sensitivity to T cell attack, overcoming melanoma treatment resistance.

Area of Science:

  • Oncology
  • Immunology
  • Cell Biology

Background:

  • Melanoma can dedifferentiate when exposed to cytotoxic T cells, potentially leading to treatment resistance.
  • It remains unclear if these dedifferentiated tumor cells pre-exist in patients or if they can be resensitized to therapy.

Purpose of the Study:

  • To investigate the existence and characteristics of pre-existing melanoma cell subpopulations resistant to immunotherapy.
  • To explore mechanisms of resistance and potential therapeutic strategies targeting these cells.

Main Methods:

  • Chronic exposure of patient-derived melanoma cell lines to antigen-specific cytotoxic T cells.
  • Analysis of NGFR (nerve growth factor receptor) expression and its correlation with treatment resistance.
  • Assessment of BDNF (brain-derived neurotrophic factor) role in T cell resistance.
  • Correlation of NGFR signature with anti-PD-1 therapy resistance in melanoma patients.
  • In vitro and in vivo studies using pharmacologic NGFR inhibition.

Main Results:

  • A pre-existing NGFR-high (NGFRhi) melanoma cell population was significantly enriched upon T cell exposure.
  • NGFRhi cells exhibited resistance to T cells recognizing differentiation and non-differentiation antigens, as well as BRAF/MEK inhibitors.
  • NGFRhi cells induced BDNF, contributing to T cell resistance, with NGFR itself also playing a role.
  • In patients, an intrinsic NGFR signature predicted resistance to anti-PD-1 therapy, and NGFRhi fractions were linked to immune exclusion.
  • Pharmacologic NGFR inhibition restored tumor sensitivity to T cell attack in vitro and in xenografts.

Conclusions:

  • A stable, pre-existing, multitherapy-refractory melanoma subpopulation characterized by high NGFR expression exists.
  • This NGFRhi subpopulation contributes to intrinsic resistance to immunotherapies.
  • Targeting and eliminating NGFRhi cells is crucial for overcoming melanoma resistance and improving immunotherapy outcomes.

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