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Concomitant type I IFN and M-CSF signaling reprograms monocyte differentiation and drives pro-tumoral arginase production.

ABSTRACT: BACKGROUND:Type I IFN-based therapies against solid malignancies have yielded only limited success. How IFN affects tumor-associated macrophage (TAM) compartment to impact the therapeutic outcomes are not well understood. METHODS:The effect of an IFN-inducer poly(I:C) on tumor-infiltrating monocytes and TAMs were analyzed using a transplantable mouse tumor model (LLC). In vitro culture systems were utilized to study the direct actions by poly(I:C)-IFN on differentiating monocytes. RESULTS:We found that poly(I:C)-induced IFN targets Ly6C+ monocytes and impedes their transition into TAMs. Such an effect involves miR-155-mediated suppression of M-CSF receptor expression, contributing to restricting tumor growth. Remarkably, further analyses of gene expression profile of IFN-treated differentiating monocytes reveal a strong induction of Arg1 (encoding arginase-1) in addition to other classical IFN targets. Mechanistically, the unexpected Arg1 arm of IFN action is mediated by a prolonged STAT3 signaling in monocytes, in conjunction with elevated macrophage colony-stimulating factor (M-CSF) signaling. Functionally, induction of ARG1 limited the therapeutic effect of IFN, as inhibition of arginase activity could strongly synergize with poly(I:C) to enhance CD8+ T cell responses to thwart tumor growth in mice. CONCLUSIONS:Taken together, we have uncovered two functionally opposing actions by IFN on the TAM compartment. Our work provides significant new insights on IFN-mediated immunoregulation that may have implications in cancer therapies.

SUBMITTER: Tong Y

PROVIDER: S-EPMC6354658 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Concomitant type I IFN and M-CSF signaling reprograms monocyte differentiation and drives pro-tumoral arginase production.

Tong Yuanyuan Y Zhou Luyang L Yang Limin L Guo Panpan P Cao Yanlan Y Qin F Xiao-Feng FX Liu Jianghuai J

EBioMedicine 20181207

<h4>Background</h4>Type I IFN-based therapies against solid malignancies have yielded only limited success. How IFN affects tumor-associated macrophage (TAM) compartment to impact the therapeutic outcomes are not well understood.<h4>Methods</h4>The effect of an IFN-inducer poly(I:C) on tumor-infiltrating monocytes and TAMs were analyzed using a transplantable mouse tumor model (LLC). In vitro culture systems were utilized to study the direct actions by poly(I:C)-IFN on differentiating monocytes. ...[more]

PMID: 30528455

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Dataset Information

Concomitant type I IFN and M-CSF signaling reprograms monocyte differentiation and drives pro-tumoral arginase production.

Publications

Concomitant type I IFN and M-CSF signaling reprograms monocyte differentiation and drives pro-tumoral arginase production.

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