Targeting macrophage priming by polyphyllin VII triggers anti-tumor immunity via STING-governed cytotoxic T-cell infiltration in lung cancer

Jinglu Yu,Haibin Deng,Zhenye Xu

doi:10.1038/s41598-020-77800-w

Abstract

Stimulator of interferon genes (STING) controlled innate immune pathway is essential for host defense against pathogenic infection and effective anti-tumor adaptive immunity initiation. Although macrophages transformed across diverse phenotypes play crucial roles in anti-tumor immune response, events determining this transformation and the host-intrinsic role of STING in this process remain controversial. Here we report how STING signaling acts as a key switch to dominate the gene expression patterns of macrophage transformation for promoting priming and releasing immunosuppression. Furthermore, polyphyllin VII, a potential STING agonist, exerts anti-tumor efficacy upon macrophages priming and subsequent cytotoxic T lymphocytes intratumoral infiltration. Meanwhile, the simultaneous PD-L1 amplification on macrophages in response to PP VII is also ruled by STING, thus PP VII may benefit immune-checkpoint blockade therapy for combining. Moreover, PP VII suppresses carcinogenesis upon restraining the immunosuppressed macrophage transformation. This is due to the boosted STING that negatively regulates a STAT3 propagated crosstalk between immune cells and tumor cells. Overall, PP VII-stimulated STING in macrophages provides a paradigm for anti-tumor, and if possible, anti-infection immunotherapy.

Highlights

Despite considerable advances in treatment of lung cancer in recent years, the prognosis of patients remains very poor[1,2]
Lipopolysaccharide (LPS), another commonly used stimulator for M1 macrophage polarization transmitted by Toll-like receptor 4 (TLR4)[37], did not induce programmed death ligand-1 (PD-L1) expression, which is distinct from IFN-γ
Compared to combination with cytokines, Polyphyllin VII (PP VII) alone slightly induced iNOS and stimulator of interferon genes (STING) expression, had no influence on STAT3 activity (Fig. 1g). These data suggest that PP VII activates the STING/TBK1/IRF3 pathway and subsequently augments M1 macrophage polarization, as well as suppresses Stat[3] phosphorylation, this correlates with STING protein expression rather than induction of DNA damage

Summary

Introduction

Despite considerable advances in treatment of lung cancer in recent years, the prognosis of patients remains very poor[1,2]. Macrophages are a major component of the leukocyte infiltrated in the T IME10 They are transformed upon exposed to multiple signals of local or systemic origin endow them environmentally sensitive cells with high plasticity, subsequently give response to the extracellular milieu in shaping the immune environment[11]. Given that they are extremely versatile cells performing pleiotropic cellular programs, such as phagocytosis of pathogens, processing and presentation of antigens, secretion of chemicals to recruit and reshape other cells, considered a promising Intervention target for transforming the immunosuppressive TIME into an immune activated o ne[10,11,12,13]. The question is whether there is an intersection between the mechanism of switching macrophages transformation and inducing PD-L1 production

Methods

Results

Conclusion