IL-27 Gene Therapy Induces Stat3-Mediated Expansion of CD11b+Gr1+ Myeloid Cells and Promotes Accumulation of M1 Macrophages in the Tumor Microenvironment

Author:

Zhu Jianmin1ORCID,Yu Jianyu1ORCID,Hu Aiyan1ORCID,Liu Jin-Qing1,Pan Xueliang2ORCID,Xin Gang3,Carson William E.4,Li Zihai3ORCID,Yang Yiping35,Bai Xue-Feng1ORCID

Affiliation:

1. *Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH

2. †Center for Biostatistics, College of Medicine, The Ohio State University, Columbus, OH

3. ‡Institute for Immuno-Oncology, Comprehensive Cancer Center, The Ohio State University, Columbus, OH

4. §Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, OH

5. ¶Division of Hematology, Comprehensive Cancer Center, The Ohio State University, Columbus, OH

Abstract

Abstract IL-27 is a pleiotropic cytokine that exhibits stimulatory/regulatory functions on multiple lineages of immune cells and has a potential to be used as a therapeutic for cancer. We have recently demonstrated that administration of IL-27 producing adeno-associated virus (AAV-IL-27) exhibits potent inhibition of tumor growth in mouse models. In this study, we demonstrate that AAV-IL-27 treatment leads to significant expansion of CD11b+Gr1+ myeloid cells. AAV-IL-27–induced expansion of CD11b+Gr1+ cells is IL-27R–dependent and requires Stat3 signaling, but it is inhibited by Stat1 signaling. AAV-IL-27 treatment does not increase the self-renewal capacity of CD11b+Gr1+ cells but induces significant expansion of Lin−Sca1+c-Kit+ (LSK) and granulocyte–monocyte progenitor cells. Despite exhibiting significant suppression of T cells in vitro, IL-27–induced CD11b+Gr1+ cells lost the tumor-promoting activity in vivo and overall play an antitumor role. In tumors from AAV-IL-27–treated mice, CD11b+Gr1+ cells are largely F4/80+ and express high levels of MHC class I/II and M1 macrophage markers. Thus, IL-27 gene therapy induces Stat3-mediated expansion of CD11b+Gr1+ myeloid cells and promotes accumulation of M1 macrophages in the tumor microenvironment.

Funder

HHS | National Institutes of Health

Publisher

The American Association of Immunologists

Subject

Immunology,Immunology and Allergy

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