Activating cGAS-STING pathway for the optimal effect of cancer immunotherapy

Anping Li,Yongping Song,Kongming Wu,Shuang Qin,Ming Yi,Qian Chu

doi:10.1186/s13045-019-0721-x

Abstract

During tumor progression, a subset of cancer cells escape from immune surveillance and eventually develop into measurable tumor mass. Cancer immunotherapy eradicates tumor cells by enhancing multiple steps in cancer-immunity cycle including antigen presentation, T cell priming, activation, and immune killing activity. Immunotherapy has been verified as an effective strategy in multiple cancers, but some problems still exist in actual clinical practice such as frequent primary and adaptive resistance. Combination with other adjuvant therapies gives us a new perspective to overcome the emerging obstacles in immunotherapy application. Recently, a series of studies demonstrated that the vital component of host innate immunity — cGAS-STING pathway might play an important role in anti-cancer immunity. It is generally acknowledged that the downstream signals of cGAS-STING especially type I interferon (IFN) bridge innate immunity and adaptive immunity. Given the functions of type I IFN in promoting the maturation and migration of dendritic cells, enhancing cytotoxic T lymphocyte- or natural killer cell-mediated cytotoxicity effect, and protecting effector cells from apoptosis, we believe cGAS-STING agonist might be used as sensitizer for multiple immunotherapies such as cancer vaccine, immune checkpoint blockade, and chimeric antigen receptor T cell therapy. In this review, we highlight the latest understanding of cGAS-STING pathway and the advances of the combination therapy of STING agonist and immunotherapy.

Highlights

Accumulating mutations in cancer cells render malignant transformation, and activate host’s anti-tumor immune response
We proposed that Cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING)-induced type I IFN might promote the survival of memory tumor-specific CTLs
We proposed that STING agonist could boost the efficacy of Chimeric antigen receptor T cell (CAR-T)-induced in situ cancer vaccine and initiate durable systemic anti-tumor immune response

Summary

Introduction

Accumulating mutations in cancer cells render malignant transformation, and activate host’s anti-tumor immune response. Stimulated by cytosolic DNA, active cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway stimulates the expression of type I interferon (IFN) in cancer cells or DCs, initiating innate anti-cancer immunity [13–16]. CGAS-STING agonists induce cancer cell senescence but enhance adaptive anti-cancer immunity which would synergize with immunotherapies [21–24].

Results

Conclusion