Type ? Interferon-mediated Regulation Of Monocytes Development And Its Implincations In DsRNA-based Cancer Immunotherapy

Type I IFN was initially characterized as an early line of defense to viral pathogens in innate immunity.Over decades of studies,it had been further shown to possessanti-proliferative and immunomodulatory activities.Such activities prompted the introduction of type I IFN into clinical applications against cancers.More recently,pattern recognition receptor-based IFN-inducers such as poly I:C has shown promising anti-tumor activities,possibly via the actions of IFN as well as other pro-inflammatory cytokines.More extensive understandings to the mechanisms regulating the anti-tumor activities by IFN-inducers would therefore have therapeutic implications.It has become more recognized that the anti-tumor activities by IFN and its inducers are mediated by immunoregulation.These reagents can directly or indirectly regulate the function of a number of immune cell types,including DCs,T cells and NK cells,all representing important regulators of anti-tumor immunity.In this regard,it is worth noting that despite the well-recognized role of tumor-associated macrophages(TAMs)in tumor progression,the changes in such cell compartment under the treatment of IFN or its inducers have not been studied extensively.Using a mouse model with implantation of syngenic tumors,we found that systemic treatment(i.p.)of polyI:C leads to a moderate inhibition of tumor growth,associated with a reduced density of TAMs.These results has promote us to further hypothesize that the type I IFN induced by polyI:C functions to slow tumor growth by inhibiting the differentiation of monocytes into tumor-associated macrophages.Indeed,we showed that the type I IFN inhibits the differentiation of both mouse and human monocytes into macrophages under the macrophage-driving cue of colony-stimulating factor 1(CSF1).We further demonstrated via a series of experiments that IFN elicits an mir-15 5-driven,direct suppression of CSF-1R expression to inhibit monocytes to macrophages differentiation,and that the activity of such a regulatory axis correlated with tumor inhibition by polyI:C.To our great surprise,although IFN-inhibited the monocyte-macrophage transition,it markedly up-regulated the expression of several immunosuppressive genes,most notably the prototypical M2 macrophage genes including Argl(encoding arginase1)in both mouse and human monocytes.Furthermore,induction of Argl was clearly observed in tumors from polyI:C treated mice.Therefore,poly(I:C)-IFN appears to drive a previously unrecognized,immunosuppressive program in monocytes.Such a program may limit the effectiveness of poly(I:C)-IFN therapy.Consistent with this notion,poly(I:C)and arginase inhibitor NOR-NOHA elicited a clear synergistic effect on inhibition of implanted tumor growth.Taken together,these results has suggested a seemingly paradoxical regulation of TAM numbers and functionality by poly(I:C)-based immunotherapy,suggesting that the therapeutic effects on tumors could be enhanced by combinatorial approaches.More detailed mechanistic insights underlying such paradoxical regulation warrant further studies.