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Researchers at the Wistar Institute and the Medical University of Vienna say they have identified the role of tumor-infiltrating or tumor-associated B cells (TABs) in melanoma progression and resistance to targeted therapy. A molecular mechanism that governs the interactions between TABs and tumor cells has now been clarified and this could lead to a potential new therapeutic strategy for combating tumors resistant to treatment, according to the scientists.
Their study (“Tumor-Associated B-Cells Induce Tumor Heterogeneity and Therapy Resistance”) appears online in Nature Communications.
Researchers know that the tumor microenvironment (i.e., the complex of stroma-derived cells and immune cells surrounding cancer cells) greatly influences melanoma progression and therapy resistance. The Nature Communications study shows how TABs, which account for up to one third of all immune cells that infiltrate the tumor, can promote tumor heterogeneity and cancer stem cell-like populations that are associated with drug resistance.
“We describe here a mechanism of acquired drug resistance through the tumor microenvironment, which is mediated by human tumor-associated B cells. Human melanoma cells constitutively produce the growth factor FGF-2 [fibroblast growth factor-2], which activates tumor-infiltrating B cells to produce the growth factor IGF-1 [insulin-like growth factor-1]. B-cell-derived IGF-1 is critical for resistance of melanomas to BRAF and MEK inhibitors due to emergence of heterogeneous subpopulations and activation of FGFR-3,” write the investigators.
“Consistently, resistance of melanomas to BRAF and/or MEK inhibitors is associated with increased CD20 and IGF-1 transcript levels in tumors and IGF-1 expression in tumor-associated B cells. Furthermore, first clinical data from a pilot trial in therapy-resistant metastatic melanoma patients show anti-tumor activity through B-cell depletion by anti-CD20 antibody. Our findings establish a mechanism of acquired therapy resistance through tumor-associated B cells with important clinical implications.”
“Our results point to an important cancer-promoting function of tumor-infiltrating B cells and elucidate the molecular 'conversation' between B cells and melanoma cells, which eventually favors tumor progression and therapy resistance,” said lead researcher Meenhard Herlyn, D.V.M., D.Sc., Caspar Wistar Professor and director of The Wistar Institute Melanoma Research Center.
Dr. Herlyn, Rajasekharan Somasundaram, Ph.D., research assistant professor in the Molecular and Cellular Oncogenesis Program at Wistar, Stephan N. Wagner, M.D., from the Medical University of Vienna, and colleagues used a co-culture system of melanoma cells and B cells to evaluate the reciprocal effect of the interaction between these two cell types. By using this approach, they identified those inflammatory factors produced by B cells and melanoma cells that were relevant for the interaction and can be used as potential targets for novel therapy.
The researchers also analyzed tissue samples from melanoma patients and confirmed the prevalence of TABs in advanced, therapy-resistant tumors tissues. Additionally, these tissues showed increased expression of IGF-1 and FGF receptor 3 (FGFR-3), identified as crucial players in the B cell–melanoma cross-talk and potential new therapeutic targets for metastatic melanoma.
The team’s research also included a pilot multicenter clinical trial to evaluate the therapeutic potential of B-cell depletion in therapy-resistant advanced melanoma patients using a monoclonal antibody that specifically binds to CD20, a molecule present on the surface of these cells, thereby causing their death.
“Our results describe a novel mechanism of drug resistance in melanoma induced by tumor-infiltrating B cells,” said Dr. Somasundaram, first author and one of the corresponding authors of the paper. “This study also provides a clinical basis for developing a novel therapeutic approach for advanced melanoma based on targeting tumor infiltrating B cells.”
