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

  • Int J Radiat Oncol Biol Phys. 2023 Mar 15;115(4):957-971. doi: 10.1016/j.ijrobp.2022.10.028.
Shotaro Nakajima  1 ,  Kosaku Mimura  2 ,  Akinao Kaneta  3 ,  Katsuharu Saito  3 ,  Masanori Katagata  3 ,  Hirokazu Okayama  3 ,  Motonobu Saito  3 ,  Zenichiro Saze  3 ,  Yohei Watanabe  3 ,  Hiroyuki Hanayama  3 ,  Takeshi Tada  3 ,  Wataru Sakamoto  3 ,  Tomoyuki Momma  3 ,  Hiromasa Ohira  4 ,  Koji Kono  5
Affiliations
  • 1. Departments of Multidisciplinary Treatment of Cancer and Regional Medical Support; Gastrointestinal Tract Surgery.
  • 2. Gastrointestinal Tract Surgery; Blood Transfusion and Transplantation Immunology.
  • 3. Gastrointestinal Tract Surgery.
  • 4. Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan.
  • 5. Departments of Multidisciplinary Treatment of Cancer and Regional Medical Support; Gastrointestinal Tract Surgery. Electronic address: [email protected].
PMID: 36368436 DOI: 10.1016/j.ijrobp.2022.10.028
Abstract

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 interferon 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 radiation in ESCC cell lines. We also quantified the association between tumor cell-intrinsic expression of cGAS-STING and infiltrations 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.

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