Circulating Exosomes Inhibit B Cell Proliferation and Activity.

Jan C Schroeder,Inga J Beccard,Simon Laban,Marie-Nicole Theodoraki,Sandra S Jeske,Johannes Doescher,Thomas K Hoffmann,Lisa Puntigam,Cornelia Brunner,Patrick J Schuler,Linda Hofmann

doi:10.3390/cancers12082110

Jan C Schroeder, Inga J Beccard + Show 9 more

Open Access

https://doi.org/10.3390/cancers12082110

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Journal: Cancers	Publication Date: Jul 29, 2020
Citations: 22	License type: CC BY 4.0

Affiliation: University of Ulm

Abstract

(1) Background: Head and neck squamous cell carcinoma (HNSCC) is characterized by a distinctive suppression of the anti-tumor immunity, both locally in the tumor microenvironment (TME) and the periphery. Tumor-derived exosomes mediate this immune suppression by directly suppressing T effector function and by inducing differentiation of regulatory T cells. However, little is known about the effects of exosomes on B cells. (2) Methods: Peripheral B cells from healthy donors and HNSCC patients were isolated and checkpoint receptor expression was analyzed by flow cytometry. Circulating exosomes were isolated from the plasma of HNSCC patients (n = 21) and healthy individuals (n = 10) by mini size-exclusion chromatography. B cells from healthy individuals were co-cultured with isolated exosomes for up to 4 days. Proliferation, viability, surface expression of checkpoint receptors, and intracellular signaling were analyzed in B cells by flow cytometry. (3) Results: Expression of the checkpoint receptors PD-1 and LAG3 was increased on B cells from HNSCC patients. The protein concentration of circulating exosomes was increased in HNSCC patients as compared to healthy donors. Both exosomes from healthy individuals and HNSCC patients inhibited B cell proliferation and survival, in vitro. Surface expression of inhibitory and stimulatory checkpoint receptors on B cells was modulated in co-culture with exosomes. In addition, an inhibitory effect of exosomes on B cell receptor (BCR) signaling was demonstrated in B cells. (4) Conclusions: Plasma-derived exosomes show inhibitory effects on the function of healthy B cells. Interestingly, these inhibitory effects are similar between exosomes from healthy individuals and HNSCC patients, suggesting a physiological B cell inhibitory role of circulating exosomes.

Highlights

With the recent advent of effective cancer immunotherapy, the interaction between tumor cells and the immune system has gained a lot of attention
Before investigating the effects of exosomes on healthy B cells, we looked for differences in checkpoint receptor expression between B cells isolated from healthy individuals and Head and neck squamous cell carcinoma (HNSCC) patients
We found an increase in the frequency of PD-1+ and LAG3+ B cells in the plasma of HNSCC patients as compared to healthy individuals (Figure 1), which parallels findings from studies of hepatocellular and thyroid cancer patients [18,21,22]

Summary

Introduction

With the recent advent of effective cancer immunotherapy, the interaction between tumor cells and the immune system has gained a lot of attention. Tumors inhibit the anti-tumor immune response [1], and tumor entities differ with regard to their immune-suppressive properties. Squamous Cell Carcinoma (HNSCC) is classified as one of the most immune-suppressive cancers, making it a pivotal candidate for immunotherapy [2]. In HNSCC, several mechanisms contribute to tumor immune escape: (I) downregulation of antigen expression, (II) upregulation of immune-suppressive mediators such as PD-L1, and (III). While tumor-infiltrating effector cells such as T, B, NK, and dendritic cells are functionally impaired in HNSCC [6,7], regulatory T cells (Treg) are actively recruited and contribute to the immune escape [8]

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