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Tumor-associated B-cells induce tumor heterogeneity and therapy resistance

Rajasekharan Somasundaram1, Gao Zhang2, Mizuho Fukunaga-Kalabis2

  • 1The Wistar Institute, Philadelphia, PA, 19104, USA. Shyam@wistar.org.

Nature Communications
|September 21, 2017
PubMed

Insights

Tumor-associated B cells drive resistance to BRAF inhibitors in melanoma by producing IGF-1. Depleting these B cells with anti-CD20 antibodies shows promise in treating therapy-resistant metastatic melanoma.

Area of Science:

  • Oncology
  • Immunology
  • Cancer Biology

Background:

  • BRAFV600E inhibitors are effective melanoma treatments, but acquired drug resistance limits their long-term efficacy.
  • Drug resistance often arises from the emergence of resistant tumor subpopulations within the tumor microenvironment.

Purpose of the Study:

  • To elucidate a mechanism of acquired drug resistance in melanoma mediated by tumor-associated B cells.
  • To investigate the role of B-cell-derived growth factors in resistance to BRAF and MEK inhibitors.

Main Methods:

  • Analysis of melanoma cell-B cell interactions and growth factor production (FGF-2, IGF-1).
  • Assessment of B-cell involvement in resistance to BRAF and MEK inhibitors.
  • Correlation of CD20 and IGF-1 transcript levels with treatment resistance.
  • Evaluation of anti-tumor activity of B-cell depletion therapy (anti-CD20 antibody) in a pilot clinical trial.

Main Results:

  • Melanoma cells produce FGF-2, activating tumor-infiltrating B cells to produce IGF-1.
  • B-cell-derived IGF-1 promotes melanoma resistance to BRAF and MEK inhibitors by fostering heterogeneous subpopulations and activating FGFR-3.
  • Increased CD20 and IGF-1 levels in tumors correlate with resistance.
  • B-cell depletion using anti-CD20 antibody demonstrated anti-tumor activity in therapy-resistant metastatic melanoma patients.

Conclusions:

  • Tumor-associated B cells mediate acquired resistance to BRAF and MEK inhibitors in melanoma through IGF-1 production.
  • Targeting B cells represents a potential therapeutic strategy for overcoming drug resistance in metastatic melanoma.

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