PEG-rIL-10 treatment decreases FoxP3+ Tregs despite upregulation of intratumoral IDO. (2nd July 2016)

• Record Type: Journal Article
• Authors: Chan, Ivan H.; Wu, Victoria; Bilardello, Melissa; Jorgenson, Brett; Bal, Harminder; McCauley, Scott; Van Vlasselaer, Peter; Mumm, John B.
• Is Part Of: Oncoimmunology. Volume 5:Number 7(2016)
• Publication Date: 2016-07-02
• Subjects: FoxP3+ -- IDO -- IL-10 -- IL-2 -- immunoncology -- TGFβ -- Treg polarization; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2016.1197458
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: IL-10 has been classically defined as a broad-spectrum immunosuppressant and is thought to facilitate the development of regulatory CD4 + T cells. IL-10 is believed to represent one of the major suppressive factors secreted by IDO + FoxP3 + CD4 + Tregs . Contrary to this view, we have previously reported that PEGylated recombinant IL-10 (PEG-rIL-10) treatment of mice induces potent IFNγ and CD8 + T-cell-dependent antitumor immunity. This hypothesis is currently being tested in clinical trials and we have reported that treatment of cancer patients with PEG-rHuIL-10 results in inhibition and regression of tumor growth as well as increased serum IFNγ. We have continued to assess PEG-rIL-10's pleiotropic effects and report that treatment of tumor-bearing mice and humans with PEG-rIL-10 increases intratumoral indoleamine 2, 3-dioxygenase (IDO) in an IFNγ-dependent manner. This should result in an increase in Tregs, but paradoxically our data illustrate that PEG-rIL-10 treatment of mice reduces intratumoral FoxP3 + CD4 + T cells in an IDO-independent manner. Additional investigation indicates that PEG-rIL-10 inhibits TGFβ/IL-2-dependent in vitro polarization of FoxP3 + CD4 + Tregs and potentiates IFNγ + T-bet + CD4 + T cells. These data suggest that rather than acting as an immunosuppressant, PEG-rIL-10 may counteract the FoxP3 + CD4 + Treg suppressive milieu in tumor-bearing mice and humans, thereby further facilitating PEG-rIL-10's potent antitumor immunity.