STING: a master regulator in the cancer-immunity cycle

Yuanyuan Zhu,Xiang An,Yu Qiao,Tongsen Zheng,Xiao Zhang,Xiaobo Li

doi:10.1186/s12943-019-1087-y

Yuanyuan Zhu, Xiang An + Show 4 more

Open Access

https://doi.org/10.1186/s12943-019-1087-y

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Abstract

The aberrant appearance of DNA in the cytoplasm triggers the activation of cGAS-cGAMP-STING signaling and induces the production of type I interferons, which play critical roles in activating both innate and adaptive immune responses. Recently, numerous studies have shown that the activation of STING and the stimulation of type I IFN production are critical for the anticancer immune response. However, emerging evidence suggests that STING also regulates anticancer immunity in a type I IFN-independent manner. For instance, STING has been shown to induce cell death and facilitate the release of cancer cell antigens. Moreover, STING activation has been demonstrated to enhance cancer antigen presentation, contribute to the priming and activation of T cells, facilitate the trafficking and infiltration of T cells into tumors and promote the recognition and killing of cancer cells by T cells. In this review, we focus on STING and the cancer immune response, with particular attention to the roles of STING activation in the cancer-immunity cycle. Additionally, the negative effects of STING activation on the cancer immune response and non-immune roles of STING in cancer have also been discussed.

Highlights

William Coley, the father of immunotherapy, began using Streptococcus pyogenes to treat patients with unresectable tumors in 1891 when chemotherapy and radiotherapy were not available [1]
These results show that activation of the Stimulator of interferon genes (STING) pathway in Antigenpresenting cells (APC) and other immune cells can induce the expression of cytokines and thereby promote T-cell trafficking
Authors revealed that non-hematopoietic cells play important roles in the infiltration of CD8+ T cells into tumor microenvironment by employing bone morrow chimeric mice models, they did not show the direct evidence to illustrate the accurate roles of STING activation in endothelial cells in the process of T cell infiltration [59]. These results revealed an unexpected role of endothelial cells within the tumor microenvironment in cancer immunity, and suggested that STING activation in endothelial cells is necessary for the infiltration of Cytotoxic T lymphocytes (CTL)

Summary

Introduction

William Coley, the father of immunotherapy, began using Streptococcus pyogenes to treat patients with unresectable tumors in 1891 when chemotherapy and radiotherapy were not available [1]. Cytosolic DNA triggers the activation of cGAScGAMP-STING signaling This signaling plays critical roles in the host defense against microbial infection, and has been demonstrated to be involved in the antitumor immune response, and numerous studies have suggested that the activation of STING is a novel and promising strategy to treat cancer. STING induces the production of type I IFN and activates the innate immune system Whether caused by leakage from the nucleus or mitochondria or induced by viruses or bacteria, cytoplasmic DNA is a danger signal. As the first applied STING agonist in cancer immunotherapy, DMXAA showed promising antitumor activity in mice, but it failed in clinical trials because DMXAA does not preferentially bind to human STING [42, 43]. These STING agonists are nonpenetrating [68], they must

Provoke abscopal immunity

Refractory Tumors

Advanced or Recurrent Completed Solid Tumors

Solid tumors Lymphomas