B Cells Promote Tumor Progression via STAT3 Regulated-Angiogenesis

Chunmei Yang,Jiehui Deng,Wang Zhang,Dave S B Hoon,Veronica Jove,Hua Yu,Heehyoung Lee,Sumanta Pal,Stephen Forman,Mark Wakabayashi,Joao P B Viola

doi:10.1371/journal.pone.0064159

Abstract

The role of B cells in cancer and the underlying mechanisms remain to be further explored. Here, we show that tumor-associated B cells with activated STAT3 contribute to tumor development by promoting tumor angiogenesis. B cells with or without Stat3 have opposite effects on tumor growth and tumor angiogenesis in both B16 melanoma and Lewis Lung Cancer mouse models. Ex vivo angiogenesis assays show that B cell-mediated tumor angiogenesis is mainly dependent on the induction of pro-angiogenic gene expression, which requires Stat3 signaling in B cells. Furthermore, B cells with activated STAT3 are mainly found in or near tumor vasculature and correlate significantly with overall STAT3 activity in human tumors. Moreover, the density of B cells in human tumor tissues correlates significantly with expression levels of several STAT3-downstream pro-angiogenic genes, as well as the degree of tumor angiogenesis. Together, these findings define a novel role of B cells in promoting tumor progression through angiogenesis and identify STAT3 in B cells as potential therapeutic target for anti-angiogenesis therapy.

Highlights

The type and density of immune cells in the tumor tissue have recently been shown to be one of the most reliable parameters for predicting a patient’s clinical outcome in certain types of cancer [1,2,3,4]
Our study further reveals a previously unrecognized role of B cell signal transducer and activator of transcription 3 (STAT3) in accelerating tumor progression through increasing angiogenesis
Commonly present as aggregates with other immune cells [10], B cells may contribute to a network with other cells to promote tumor angiogenesis in a STAT3-dependent manner

Summary

Introduction

The type and density of immune cells in the tumor tissue have recently been shown to be one of the most reliable parameters for predicting a patient’s clinical outcome in certain types of cancer [1,2,3,4]. The density of T cells in colorectal tumor tissues represents a better prognostic indicator for patient outcome than current staging systems [2,3]. B cellmediated antibody production against tumor antigens is associated with better clinical outcome in human medullary breast carcinoma [12]. While these studies demonstrate the beneficial effect of B cells on anti-cancer immunity, a cancer-promoting role of B cells has been recognized

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Results

Conclusion