Spatiotemporal Analysis of B Cell- and Antibody Secreting Cell-Subsets in Human Melanoma Reveals Metastasis-, Tumor Stage-, and Age-Associated Dynamics.

Minyi Chen,Martin Simon,Erika Richtig,Christine Wagner,Franziska Werner,Stephan N Wagner,Kirsten D Mertz,Johannes Griss

doi:10.3389/fcell.2021.677944

Minyi Chen, Martin Simon + Show 6 more

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https://doi.org/10.3389/fcell.2021.677944

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Abstract

Background: The role of tumor-associated B cells in human cancer is only starting to emerge. B cells typically undergo a series of developmental changes in phenotype and function, however, data on the composition of the B cell population in human melanoma are largely absent including changes during tumor progression and their potential clinical significance.Methods: In this study, we compared the number and distribution of six major B cell and antibody secreting cell subpopulations outside tertiary lymphoid structures in whole tumor sections of 154 human cutaneous melanoma samples (53 primary tumors without subsequent metastasis, 44 primary tumors with metastasis, 57 metastatic samples) obtained by seven color multiplex immunohistochemistry and automated tissue imaging and analysis.Results: In primary melanomas, we observed the highest numbers for plasmablast-like, memory-like, and activated B cell subtypes. These cells showed a patchy, predominant paratumoral distribution at the invasive tumor-stroma margin. Plasma cell-like cells were hardly detected, germinal center- and transitional/regulatory-like B cells not at all. Of the major clinicopathologic prognostic factors for primary melanomas, metastasis was associated with decreased memory-like B cell numbers and a higher age associated with higher plasmablast-like cell numbers. When we compared the composition of B cell subpopulations in primary melanomas and metastatic samples, we found a significantly higher proportion of plasma cell-like cells at distant metastatic sites and a higher proportion of memory-like B cells at locoregional than distant metastatic sites. Both cell types were detected mainly in the para- and intratumoral stroma.Conclusion: These data provide a first comprehensive and comparative spatiotemporal analysis of major B cell and antibody secreting cell subpopulations in human melanoma and describe metastasis-, tumor stage-, and age-associated dynamics, an important premise for B cell-related biomarker and therapy studies.

Highlights

The tumor immune microenvironment critically regulates tumor initiation, progression and response to therapy
Phenotypic analysis showed that the tumor microenvironment contains CD20+ tumorassociated B cells (TAB) and CD138+ or IgA+CD138+ antibody secreting cells (ASC), which are primarily found at the invasive tumor-stroma margin (Erdag et al, 2012; Bosisio et al, 2016; Griss et al, 2019)
We have recently shown that B cells from human melanoma are essential to sustain inflammation and CD8+ T cell numbers in the tumor microenvironment and can directly augment T cell activation by immune checkpoint blockade

Summary

Introduction

The tumor immune microenvironment critically regulates tumor initiation, progression and response to therapy (reviewed in Binnewies et al, 2018). Syngeneic mouse models revealed both pro- as well as anti-tumorigenic effects of B cells (reviewed in Fremd et al, 2013), while advanced models such as genetically engineered mouse models or xenotransplantation models suffer from inadequate tumor infiltration by B cells or other immune cells of the tumor microenvironment (Hooijkaas et al, 2012) These data underline the importance of studies in human tissue samples. Initial studies on the association of TAB numbers in primary human melanomas with patient survival employed CD20-immunostaining and reported on higher numbers in histological subtypes with a worse prognosis (Hillen et al, 2008) or on the association of higher percentages of CD20+ TAB within tumor-infiltrating lymphocytes with a worse patient prognosis (Martinez-Rodriguez et al, 2014) These data were supported by observations from melanoma metastases where a 7-marker protein signature, including CD20, negatively predicted overall and recurrence-free patient survival (Meyer et al, 2012). B cells typically undergo a series of developmental changes in phenotype and function, data on the composition of the B cell population in human melanoma are largely absent including changes during tumor progression and their potential clinical significance

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