TY - JOUR
T1 - Therapeutic activity of high-dose intratumoral IFN-β requires direct effect on the tumor vasculature
AU - Spaapen, Robbert M.
AU - Leung, Michael Y.K.
AU - Fuertes, Mercedes B.
AU - Kline, Justin P.
AU - Zhang, Long
AU - Zheng, Yan
AU - Fu, Yang Xin
AU - Luo, Xixi
AU - Cohen, Kenneth S.
AU - Gajewski, Thomas F.
N1 - Publisher Copyright:
Copyright © 2014 by The American Association of Immunologists, Inc.
PY - 2014/10/15
Y1 - 2014/10/15
N2 - Endogenous type I IFN production after innate immune recognition of tumor cells is critical for generating natural adaptive immune responses against tumors in vivo. We recently have reported that targeting low doses of IFN-β to the tumor microenvironment using tumor-specific mAbs can facilitate antitumor immunity, which could be augmented further with PD-L1/PD-1 blockade. However, sustained high doses of type I IFNs in the tumor microenvironment, which are potently therapeutic alone, may function through distinct mechanisms. In the current report, we demonstrate that high-dose intratumoral type I IFNs indeed exerted a profound therapeutic effect in the murine B16 model, which unexpectedly did not increase T cell responses. Moreover, bone marrow chimeras revealed a role for type I IFN signaling on nonhematopoietic cells, and most of the therapeutic effect was retained in mice deficient in T, B, and NK cells. Rather, the tumor vasculature was ablated with high-dose intratumoral IFN-β, and conditional deletion of IFN-α/βR in Tie2-positive vascular endothelial cells eliminated most of the antitumor activity. Therefore, the major component of the antitumor activity of sustained high doses of type I IFNs occurs through a direct antiangiogenic effect. Our data help resolve conditions under which distinct antitumor mechanisms of type I IFNs are operational in vivo.
AB - Endogenous type I IFN production after innate immune recognition of tumor cells is critical for generating natural adaptive immune responses against tumors in vivo. We recently have reported that targeting low doses of IFN-β to the tumor microenvironment using tumor-specific mAbs can facilitate antitumor immunity, which could be augmented further with PD-L1/PD-1 blockade. However, sustained high doses of type I IFNs in the tumor microenvironment, which are potently therapeutic alone, may function through distinct mechanisms. In the current report, we demonstrate that high-dose intratumoral type I IFNs indeed exerted a profound therapeutic effect in the murine B16 model, which unexpectedly did not increase T cell responses. Moreover, bone marrow chimeras revealed a role for type I IFN signaling on nonhematopoietic cells, and most of the therapeutic effect was retained in mice deficient in T, B, and NK cells. Rather, the tumor vasculature was ablated with high-dose intratumoral IFN-β, and conditional deletion of IFN-α/βR in Tie2-positive vascular endothelial cells eliminated most of the antitumor activity. Therefore, the major component of the antitumor activity of sustained high doses of type I IFNs occurs through a direct antiangiogenic effect. Our data help resolve conditions under which distinct antitumor mechanisms of type I IFNs are operational in vivo.
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U2 - 10.4049/jimmunol.1401109
DO - 10.4049/jimmunol.1401109
M3 - Article
C2 - 25217157
AN - SCOPUS:84907495019
SN - 0022-1767
VL - 193
SP - 4254
EP - 4260
JO - Journal of Immunology
JF - Journal of Immunology
IS - 8
ER -