Int J Biol Sci 2020; 16(9):1563-1574. doi:10.7150/ijbs.41653 This issue

Research Paper

Downregulation of Nitric Oxide Collaborated with Radiotherapy to Promote Anti-Tumor Immune Response via Inducing CD8+ T Cell Infiltration

Jieyu Xu1, Yuan Luo1, Cheng Yuan1, Linzhi Han1, Qiuji Wu1, Liexi Xu1, Yuke Gao1, Yingming Sun1, Shijing Ma1, Guiliang Tang1, Shuying Li1, Wenjie Sun1, Yan Gong2✉, Conghua Xie1,3,4✉

1. Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
2. Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China
3. Hubei Key Laboratory of Tumour Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China
4. Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China

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Citation:
Xu J, Luo Y, Yuan C, Han L, Wu Q, Xu L, Gao Y, Sun Y, Ma S, Tang G, Li S, Sun W, Gong Y, Xie C. Downregulation of Nitric Oxide Collaborated with Radiotherapy to Promote Anti-Tumor Immune Response via Inducing CD8+ T Cell Infiltration. Int J Biol Sci 2020; 16(9):1563-1574. doi:10.7150/ijbs.41653. Available from https://www.ijbs.com/v16p1563.htm

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Abstract

Graphic abstract

The production of nitric oxide (NO) is a key feature of immunosuppressive myeloid cells, which impair T cell activation and proliferation via reversibly blocking interleukin-2 receptor signaling. NO is mainly produced from L-arginine by inducible NO synthase (iNOS). Moreover, L-arginine is an essential element for T cell proliferation and behaviors. Impaired T cell function further inhibits anti-tumor immunity and promotes tumor progression. Previous studies indicated that radiotherapy activated anti-tumor immune responses in multiple tumors. However, myeloid-derived cells in the tumor microenvironment may neutralize these responses. We hypothesized that iNOS, as an important regulator of the immunosuppressive effects in myeloid-derived cells, mediated radiation resistance of cancer cells. In this study, we used 1400W dihydrochloride, a potent small-molecule inhibitor of iNOS, to explore the regulatory roles of NO in anti-tumor immunity. Radiotherapy and iNOS inhibition by 1400W collaboratively suppressed tumor growth and increased survival time, as well as increased tumor-infiltrating CD8+ T cells and specific inflammatory cytokine levels, in both lung and breast cancer cells in vivo. Our results also suggested that myeloid cell-mediated inhibition of T cell proliferation was effectively counteracted by radiation and 1400W-mediated NO blockade in vitro. Thus, these results demonstrated that iNOS was an important regulator of radiotherapy-induced antitumor immune responses. The combination of radiotherapy with iNOS blockade might be an effective therapy to improve the response of tumors to clinical radiation.

Keywords: iNOS, myeloid cells, radiotherapy, immunotherapy, tumor microenvironment