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

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.

Regulation of ROS in myeloid-derived suppressor cells through targeting fatty acid transport protein 2 enhanced anti-PD-L1 tumor immunotherapy

“…Increased ROS drives MDSCs immunosuppressive activity on T-cells as well as inhibit its differentiation to other myeloid cells [39]. Elevated level of ROS is a major characteristic of MDSCs present in tumor-bearing mice and cancer patients [40][41][42]. The immune-suppressive function of MDSCs in tumorbearing mice and cancer patients can be overcome by blocking ROS production in MDSCs [43].…”

Nitric oxide favours tumour-promoting inflammation through mitochondria-dependent and -independent actions on macrophages

“…In human malignancies, iNOS co-expression with COX-2 is often observed [ 7 , 17 ]. On the other hand, NO has been shown to impede cellular immunity, and iNOS inhibitors improve efficiency of immunotherapy and radiotherapy in mice by enhancing T and NK cell infiltration and activity [ [18] , [19] , [20] , [21] ]. The specific role of NO activity on macrophages, major drivers of tumour-associated inflammation, remains to be fully elucidated.…”

Deleterious effect of bone marrow-resident macrophages on hematopoietic stem cells in response to total body irradiation

“…Treatment of WT mice with the iNOS inhibitor 1400W, which leads to a specific inhibition of NO produced by M 58 , led to decreased percentages of both peroxynitrite + LT-HSC and apoptotic LT-HSC and to a better recovery of LT-HSC number 21 days post-TBI. A 1400W treatment combined with radiotherapy increases survival and delays or suppresses tumor growth in pancreas, lung and breast cancer 59,60 . Our results strengthened its use in cancer treatment as we showed that 1400W treatment also protected LT-HSC from potential deleterious effects of radiotherapy.…”