Abstract
The tumor-associated macrophage (TAM) serves as an immunosuppressive agent in the malignant tumor microenvironment, facilitating the development and metastasis of lung cancer. The photodynamic effect destabilizes cellular homeostasis owing to the generation of reactive oxygen species (ROS), resulting in the enhanced pro-inflammatory function of immunocytes. In our previous study, the Ce6-mediated photodynamic effect was found to have kept the viability of macrophages and to remodel them into the M1 phenotype. However, the mechanism remains unrevealed. The present study now explores the mechanism of photodynamic therapy (PDT)-mediated reprogramming of macrophages. As expected, Ce6-mediated PDT was capable of generating reactive oxygen species, which was continuously degraded, causing “low intensity” damage to DNA and thereby triggering subsequent DNA damage response in macrophages. The autophagy was thus observed in Ce6-treated macrophages and was shown to protect cells from being photodynamically apoptotic. More importantly, Ce6 PDT could activate the stimulator of interferon genes (STING) molecule, a sensor of DNA damage, which could activate the downstream nuclear factor kappa-B (NF-κB) upon activation, mediating the polarization of macrophages towards the M1 phenotype thereupon. In addition, inhibition of ROS induced by PDT attenuated the DNA damage, STING activation, and M1-phenotype reprogramming. Furthermore, the silence of the STING weakened Ce6 treatment-mediated M1 remodeling of macrophages as well. Altogether, these findings indicate the Ce6-induced photodynamic effect polarizes macrophages into an M1 phenotype through oxidative DNA damage and subsequent activation of the STING. This work reveals the crucial mechanism by which photodynamic therapy regulates the macrophage phenotype and also provides a novel intervenable signaling target for remodeling macrophages into the M1 phenotype.
Highlights
Macrophages, especially tumor-associated macrophage (TAM), are crucial immunocytes in the lung cancer microenvironment, accounting for a notable proportion, up to 50% in a variety of solid tumors (Li et al, 2018; Singhal et al, 2019; Larionova et al, 2020; Sedighzadeh et al, 2021)
The co-culture model of macrophages and LLC demonstrated that the photodynamic action induced by chlorin e6 (Ce6) promoted the inhibitory effect of LLC by macrophages, characterized by an elevated apoptosis rate of LLC (Figures 1N,O)
In vivo experiments showed significant upregulation of inducible nitric oxide synthase (iNOS), guanylate binding protein 5 (GBP5), and major histocompatibility complex-II (MHC-II) in tumor grafts of LLC-bearing mice that received Ce6 Photodynamic therapy (PDT), suggesting that more M1-phenotype macrophages may be present in tumor tissues (Figure 2)
Summary
Macrophages, especially tumor-associated macrophage (TAM), are crucial immunocytes in the lung cancer microenvironment, accounting for a notable proportion, up to 50% in a variety of solid tumors (Li et al, 2018; Singhal et al, 2019; Larionova et al, 2020; Sedighzadeh et al, 2021). Their actions in promoting immunosuppression in lung cancer by releasing immunosuppressive cytokines, reduction of cytotoxic lymphocyte infiltration, and increasing the ratio of regulatory T cells (Treg) contribute to the failure of eradicating lung cancer (Economopoulou and Mountzios, 2018; Xu et al, 2020; Sarode et al, 2020; La Fleur et al, 2021).
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