Radiation-Induced Remodeling of the Tumor Microenvironment Through Tumor Cell- Intrinsic Expression of cGAS-STING in Esophageal Squamous Cell Carcinoma

Purpose: Radiation therapy (RT) has the potential to activate the tumor-microenvironment (TME) and promote the efficacy of immune checkpoint blockade therapy. Tumor cell-intrinsic expression of cyclic GMP-AMP synthase (cGAS)-stimulator of inter-feron genes (STING) plays an important role in regulations of radiation-induced activation of immune cells in the TME. However, the role of tumor cell-intrinsic cGAS-STING in radiation-mediated remodeling of the TME in esophageal squamous cell carcinoma (ESCC) is not completely understood; thus, we investigated its effect on the radiation-mediated remodeling of the TME in ESCC.Methods: We assessed the effect of tumor cell-intrinsic cGAS-STING on the expression of mediators of the immune system, including type I interferon, T-cell chemo-attractants, colony-stimulating factor-1, and interleukin 34 (IL-34), induced by radia-tion in ESCC cell lines. We also quantified the association between tumor cell-intrinsic expression of cGAS-STING and infil-trations of immune cells, including CD8+ T cells and CD163+ M2-tumor-associated macrophages (TAMs), in ESCC tissues before and after neoadjuvant chemo-RT (n = 47).Results: We found that tumor cell-intrinsic expression of cGAS-STING was involved in radiation-induced infiltration of CD8+ T cells and expression of type I interferon and T-cell chemo-attractants in ESCC cells. Surprisingly, tumor cell-intrinsic cGAS-STING was also involved in radiation-triggered infiltration and/or M2-polarization of CD163+ TAMs and expression of IL-34, an important cytokine for recruitment and M2-polarization of TAMs, in ESCC cells. The number of CD163+ M2-TAMs was significantly associated with IL-34 expression in tumor cells in irradiated ESCC tissues.Conclusions: The tumor cell-intrinsic expression of cGAS-STING is essential for radiation-induced activation of immune cells in the TME, but it is also involved in the recruitment of tumor-promoting M2-TAMs in ESCC. Therefore, blocking of M2 -TAM infiltration by targeting IL-34 might improve the efficacy of RT and combination therapy of RT with immune checkpoint inhibitors in ESCC.(c) 2022 Elsevier Inc. All rights reserved.

Automated summary

This study investigated the role of tumor cell-intrinsic cGAS-STING in radiation-mediated remodeling of the tumor microenvironment (TME) in esophageal squamous cell carcinoma (ESCC). The findings demonstrate that cGAS-STING is involved in radiation-induced activation of immune cells and recruitment of tumor-promoting M2-tumor-associated macrophages (TAMs) through IL-34. Targeting IL-34 to block M2-TAM infiltration may improve the efficacy of radiation therapy and combination therapy with immune checkpoint inhibitors in ESCC.