Type I interferons exert anti-tumor effect via reversing immunosuppression mediated by mesenchymal stromal cells

Abstract

Mesenchymal stromal cells (MSCs) are strongly immunosuppressive via producing nitric oxide (NO) and known to migrate into tumor sites to promote tumor growth, but the underlying mechanisms remain largely elusive. Here, we found that IFNα-secreting MSCs showed more dramatic inhibition effect on tumor progression than that of IFNα alone. Interestingly, IFNα-primed MSCs could also effectively suppress tumor growth. Mechanistically, we demonstrated that both IFNα and IFNβ (type I IFNs) reversed the immunosuppressive effect of MSCs on splenocyte proliferation. This effect of type I IFNs was exerted through inhibiting iNOS (inducible nitric oxide synthase) expression in IFNγ and TNFα-stimulated MSCs. Notably, only NO production was inhibited by IFNα; production of other cytokines or chemokines tested was not suppressed. Furthermore, IFNα promoted the switch from Stat1 homodimers to Stat1-Stat2 heterodimers. Studies using the luciferase reporter system and chromatin immunoprecipitation assay revealed that IFNα suppressed iNOS transcription through inhibiting the binding of Stat1 to iNOS promoter. Therefore, the synergistic anti-tumor effects of type I IFNs and MSCs were achieved by inhibiting NO production. This study provides essential information for understanding the mechanisms of MSC-mediated immunosuppression and for the development of better clinical strategies using IFNs and MSCs for cancer immunotherapy.

Mesenchymal stromal cells and interferon α (IFNα) in cancer immunotherapy

“…(22) sought to determine the mechanisms of the antitumor effects exerted by MSCs-producing IFNα. Using the B16 mouse melanoma model, they found that IFNα acts synergistically with MSCs against tumor proliferation (22).…”

“…(22) sought to determine the mechanisms of the antitumor effects exerted by MSCs-producing IFNα. Using the B16 mouse melanoma model, they found that IFNα acts synergistically with MSCs against tumor proliferation (22). Remarkably, MSCs primed with IFNα for 24 hours prior to intramuscular co-injection with B16F0 melanoma cells in C57BL/6 mice suppressed tumor growth in vivo , whereas control MSCs slightly increased tumor growth (22).…”

“…Using the B16 mouse melanoma model, they found that IFNα acts synergistically with MSCs against tumor proliferation (22). Remarkably, MSCs primed with IFNα for 24 hours prior to intramuscular co-injection with B16F0 melanoma cells in C57BL/6 mice suppressed tumor growth in vivo , whereas control MSCs slightly increased tumor growth (22). Interestingly, IFNα inhibited IFNγ and TNFα-induced iNOS expression in MSCs, but not production of other cytokines and chemokines that are responsible for attracting immune cells into the tumor microenvironment (22).…”

“…Remarkably, MSCs primed with IFNα for 24 hours prior to intramuscular co-injection with B16F0 melanoma cells in C57BL/6 mice suppressed tumor growth in vivo , whereas control MSCs slightly increased tumor growth (22). Interestingly, IFNα inhibited IFNγ and TNFα-induced iNOS expression in MSCs, but not production of other cytokines and chemokines that are responsible for attracting immune cells into the tumor microenvironment (22). IFNα was also shown to significantly diminish NO production by IFNγ and TNFα-stimulated MSCs, which could explain the IFNα-mediated reversal of the immunosuppressive effects of MSCs (22).…”

“…Interestingly, IFNα inhibited IFNγ and TNFα-induced iNOS expression in MSCs, but not production of other cytokines and chemokines that are responsible for attracting immune cells into the tumor microenvironment (22). IFNα was also shown to significantly diminish NO production by IFNγ and TNFα-stimulated MSCs, which could explain the IFNα-mediated reversal of the immunosuppressive effects of MSCs (22). These results are consistent with the high plasticity of MSCs and easiness for their molecular manipulation that may make them suitable candidates for clinical applications.…”