TGFβ blocks IFNα/β release and tumor rejection in spontaneous mammary tumors.

Abstract:

:Type I interferons (IFN) are being rediscovered as potent anti-tumoral agents. Activation of the STimulator of INterferon Genes (STING) by DMXAA (5,6-dimethylxanthenone-4-acetic acid) can induce strong production of IFNα/β and rejection of transplanted primary tumors. In the present study, we address whether targeting STING with DMXAA also leads to the regression of spontaneous MMTV-PyMT mammary tumors. We show that these tumors are refractory to DMXAA-induced regression. This is due to a blockade in the phosphorylation of IRF3 and the ensuing IFNα/β production. Mechanistically, we identify TGFβ, which is abundant in spontaneous tumors, as a key molecule limiting this IFN-induced tumor regression by DMXAA. Finally, blocking TGFβ restores the production of IFNα by activated MHCII+ tumor-associated macrophages, and enables tumor regression induced by STING activation. On the basis of these findings, we propose that type I IFN-dependent cancer therapies could be greatly improved by combinations including the blockade of TGFβ.

journal_name

Nat Commun

journal_title

Nature communications

authors

Guerin MV,Regnier F,Feuillet V,Vimeux L,Weiss JM,Bismuth G,Altan-Bonnet G,Guilbert T,Thoreau M,Finisguerra V,Donnadieu E,Trautmann A,Bercovici N

doi

10.1038/s41467-019-11998-w

subject

Has Abstract

pub_date

2019-09-11 00:00:00

pages

4131

issue

1

issn

2041-1723

pii

10.1038/s41467-019-11998-w

journal_volume

10

pub_type

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