Interaction Networks Converging on Immunosuppressive Roles of Granzyme B: Special Niches Within the Tumor Microenvironment.

Weinan Wang,Rui Zou,Zhidong Qiu,Tianzhu He,Yu Xin,Jishuang Liu,Ye Qiu

doi:10.3389/fimmu.2021.670324

Weinan Wang, Rui Zou + Show 5 more

Open Access

https://doi.org/10.3389/fimmu.2021.670324

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Abstract

Granzyme B is a renowned effector molecule primarily utilized by CTLs and NK cells against ill-defined and/or transformed cells during immunosurveillance. The overall expression of granzyme B within tumor microenvironment has been well-established as a prognostic marker indicative of priming immunity for a long time. Until recent years, increasing immunosuppressive effects of granzyme B are unveiled in the setting of different immunological context. The accumulative evidence confounded the roles of granzyme B in immune responses, thereby arousing great interests in characterizing detailed feature of granzyme B-positive niche. In this paper, the granzyme B-related regulatory effects of major suppressor cells as well as the tumor microenvironment that defines such functionalities were longitudinally summarized and discussed. Multiplex networks were built upon the interactions among different transcriptional factors, cytokines, and chemokines that regarded to the initiation and regulation of granzyme B-mediated immunosuppression. The conclusions and prospect may facilitate better interpretations of the clinical significance of granzyme B, guiding the rational development of therapeutic regimen and diagnostic probes for anti-tumor purposes.

Highlights

Granzyme B (GrB) is a serine protease famous for its activity in proteolysis-mediated apoptosis and works as a critical effector molecule of cytotoxic lymphocytes (CLs) against pathogens during immunosurveillance [1]
The up-regulation of granzyme B was observed in a “self-feeding” process of T regulatory cells (Tregs) caused by an intercellular CC motif ligand (CCL) 1-CC chemokine receptor (CCR) 8 interaction, leading to synchronized up-regulation of FoxP3, CD39 and IL-10, which substantiated the in vivo proliferation and immunosuppressive activities of these Tregs [29]
Other than direct suppression on T cell function through the surface presentation of several immunosuppressive ligands, tumor-associated macrophages (TAMs) are an abundant source of IL-10 and transforming growth factor-b (TGF-b), both of which crosslink with the regulation network of granzyme B and might boost its levels in Tregs, B regulatory cells (Bregs), and plasmacytoid dendritic cells (pDCs) [133]

Summary

INTRODUCTION

Granzyme B (GrB) is a serine protease famous for its activity in proteolysis-mediated apoptosis and works as a critical effector molecule of cytotoxic lymphocytes (CLs) against pathogens during immunosurveillance [1]. Other than inhibiting cell function or decreasing cell viability, Tregs can directly induce apoptosis or cytolysis of B cells, antigen-presenting cells (APCs) and Teff, etc., through a GrBmediated manner [15, 16] This immunosuppression pattern may or may not require cell-to-cell contact, indicating different mechanisms that trigger granzyme B attack. Studies have shown that these iTregs expressed more granzyme B and TGF-b than their LAP negative counterpart, exerting their immunosuppressive effects via both granzyme B and TGF-b mediated mechanisms [25,26,27,28] In another case, the up-regulation of granzyme B was observed in a “self-feeding” process of Tregs caused by an intercellular CC motif ligand (CCL) 1-CC chemokine receptor (CCR) 8 interaction, leading to synchronized up-regulation of FoxP3, CD39 and IL-10, which substantiated the in vivo proliferation and immunosuppressive activities of these Tregs [29]. The immunosuppressive ability of Tregs would sometimes be reprogrammed or overwhelmed by a subtle environment, the expression and secretion of active granzyme B in Tregs could be a valuable prognostic for immunosuppressive status [30]

B Regulatory Cells

Findings

CONCLUSION