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Defining the role of melanoma-associated B cells

The tumor microenvironment is critical for tumor growth, disease progression, and treatment response. Our research group focuses on the contribution of B cells to melanoma progression and response to therapy.

B cells are part of the microenvironment of human melanomas and can originate from both tumor lymph nodes and tertiary lymphoid structures (TLS) at the tumor site. B cells and TLS have been shown to enhance T cell responses to tumor cells and predict response to therapy with antibodies that block immune checkpoints in several human cancers, including melanoma. On the other hand, B cells and TLS are also able to attenuate anti-tumor immune responses and to induce therapy resistance to BRAF and MEK inhibitors through secretion of IGF-1 and the emergence of heterogeneous melanoma subpopulations with activation of FGFR-3.

Such a functional dichotomy is also observed in several animal tumor models, in which tumor-associated B cells (TAB) can both promote and inhibit tumor growth. Similarly, we have shown in small pilot clinical trials that targeting B cells with CD20 antibodies prolonged the relapse-free interval (RFI) and overall survival (OS) of melanoma patients in early clinical stage IV (adjuvant therapy) but not in late clinical stage IV with established metastatic disease.

The cellular and molecular triggers for this functional dichotomy remain to be elucidated. An attractive hypothesis is the presence of distinct B cell subpopulations with varying functions at different disease stages, and we now have first data in human melanoma that this may indeed be the case.

Using hypothesis-driven multi-omics analyses of human tumor samples in conjunction with advanced ex vivo and in vitro functional models, we are currently investigating the cross-talk of B cell subpopulations with tumor cells. In this way, we seek to unravel relevant mechanisms that will be further validated in vivo models of the disease in collaboration with collaborative partners.

  • Pinc A, Somasundaram R, Wagner C, Hörmann M, Karanikas G, Jalili A, Bauer W, Brunner P, Grabmeier-Pfistershammer K, Gschaider M, Lai C-Y, Hsu M-Y, Herlyn M, Stingl G, Wagner SN (2012) Targeting CD20 in melanoma patients at high risk of disease recurrence. Mol Ther 20:1056-62. IF: 11.454
  • Garg G, Maurer M, Griss J, Brueggen MC, Wolf IH, Wagner C, Willi N, Mertz KD, Wagner SN (2016) Tumor associated B cells in cutaneous primary melanoma and improved clinical outcome. Human Pathol. 03.022. IF: 3.466
  • Somasundaram R, Zhang G, Fukunaga-Kalabis M, Perego M, Krepler C, Xu X, Wagner C, Hristova D, Zhang J, Tian T, Wei, Z, Liu Q, Garg K, Griss J, Hards R, Maurer M, Hafner C, Mayerhöfer M, Karanikas G, Jalili A, Bauer-Pohl V, Weihsengruber F, Rappersberger K, Koller J, Lang R, Hudgens C, Chen G, Tetzlaff M, Wu L, Tompers-Frederick D, Scolyer RA, Long GV, Damle M, Ellingsworth C, Grinman L, Choi H, Gavin BJ, Dunagin M, Raj A, Scholler N, Gross L, Beqiri M, Bennett KL, Watson I, Schaider H, Davies MA, Wargo J, Czerniecki BL, Schuchter L, Herlyn D, Flaherty K, Herlyn M, Wagner SN (2017) Tumor-associated B cells induce tumor heterogeneity and therapy resistance. Nature Commun. DOI: 10.1038/s41467-017-00452-4. IF: 14.919
  • Koelzer VH, Gisler A, Hanhart J, Griss J, Wagner SN, Willi N, Cathomas G, Sachs M, Kempf W, Thommen D, Mertz KD (2018) Digital image analysis improves precision of programmed death ligand 1 (PD-L1) scoring in cutaneous melanoma. Histopathology. doi: 10.1111/his.13528. IF: 5.087
  • Griss J, Bauer W, Wagner C, Simon M, Chen M, Grabmeier-Pfistershammer K, Maurer-Granofszky M, Roka F, Penz T, Bock C, Zhang G, Herlyn M, Glatz K, Läubli H, Mertz KD, Petzelbauer P, Wiesner T, Hartl M, Pickl W, Somasundaram S, Steinberger P, Wagner SN (2019) B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma. Nature Commun. doi: 10.1038/s41467-019-12160-2. IF: 14.919
  • Chen M, Werner F, Wagner C, Simon M, Richtig E, Mertz KD, Griss J, Wagner SN (2021) Spatiotemporal analysis of B cell- and antibody secreting cell-subsets in human melanoma reveals metastasis-, tumor stage- and age-associated dynamics. Front. Cell Dev. Biol. doi: 10.3389/fcell.2021.677944. IF: 6.684
  • Werner F, Wagner C, Simon M, Glatz K, Mertz KD, Läubli H, Griss J, Wagner SN (2021) A standardized analysis of tertiary lymphoid structures in human melanoma: disease progression- and tumor site-associated changes with germinal center alteration. Front. Immunol. doi: 10.3389/fimmu.2021.675146. IF: 7.561
  • Werner F, Wagner C, Simon M, Glatz K, Mertz KD, Läubli H, Richtig E, Griss J, Wagner SN (2021) Loss of lymphotoxin alpha-expressing memory B cells correlates with metastasis of human primary melanoma. Diagnostics 11(7), 1238, doi: 10.3390/diagnostics11071238. IF: 3.24


Characterization of melanoma subpopulations

In the past decades, clinical cancer research has mainly focused on the development and identification of drugs targeting the mass of cancer cells, while certain subpopulations have been neglected. Melanoma tumors contain multiple subpopulations, including CD20-, CD271-, CD133-, ABCB5-, and JARID1B- expressing cells. These small and temporally restricted subpopulations, some of which have tumor-initiating and/or -maintaining properties, contribute to disease resistance and/or recurrence after therapy. Therefore, these subpopulations must be targeted to completely and consistently eradicate the tumor.

  • Perego M, Maurer M, Shaffer S, Müller AC, Parapatics K, Bennett KL, Li L, Wang J, Hristova D, Shin S, Keeney, F, Liu, S, Xu X, Raj, A, Jensen JK, Wagner SN, Somasundaram R, Herlyn M (2017) Slow-cycling melanoma cells are invasive through a SerpinE2-dependent mechanism. Oncogene. doi: 10.1038/onc.2017.341. IF: 9.867