Therapeutic activity of high-dose intratumoral IFN-β requires direct effect on the tumor vasculature

Robbert M. Spaapen, Michael Y.K. Leung, Mercedes B. Fuertes, Justin P. Kline, Long Zhang, Yan Zheng, Yang Xin Fu, Xixi Luo, Kenneth S. Cohen, Thomas F. Gajewski

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4254-4260
Number of pages7
JournalJournal of Immunology
Volume193
Issue number8
DOIs
StatePublished - Jan 1 2014

Fingerprint

Tumor Microenvironment
Therapeutic Uses
Neoplasms
T-Lymphocytes
Adaptive Immunity
Therapeutics
Natural Killer Cells
Immunity
B-Lymphocytes
Endothelial Cells
Bone Marrow

ASJC Scopus subject areas

  • Immunology

Cite this

Spaapen, R. M., Leung, M. Y. K., Fuertes, M. B., Kline, J. P., Zhang, L., Zheng, Y., ... Gajewski, T. F. (2014). Therapeutic activity of high-dose intratumoral IFN-β requires direct effect on the tumor vasculature. Journal of Immunology, 193(8), 4254-4260. https://doi.org/10.4049/jimmunol.1401109

Therapeutic activity of high-dose intratumoral IFN-β requires direct effect on the tumor vasculature. / Spaapen, Robbert M.; Leung, Michael Y.K.; Fuertes, Mercedes B.; Kline, Justin P.; Zhang, Long; Zheng, Yan; Fu, Yang Xin; Luo, Xixi; Cohen, Kenneth S.; Gajewski, Thomas F.

In: Journal of Immunology, Vol. 193, No. 8, 01.01.2014, p. 4254-4260.

Research output: Contribution to journalArticle

Spaapen, RM, Leung, MYK, Fuertes, MB, Kline, JP, Zhang, L, Zheng, Y, Fu, YX, Luo, X, Cohen, KS & Gajewski, TF 2014, 'Therapeutic activity of high-dose intratumoral IFN-β requires direct effect on the tumor vasculature', Journal of Immunology, vol. 193, no. 8, pp. 4254-4260. https://doi.org/10.4049/jimmunol.1401109
Spaapen, Robbert M. ; Leung, Michael Y.K. ; Fuertes, Mercedes B. ; Kline, Justin P. ; Zhang, Long ; Zheng, Yan ; Fu, Yang Xin ; Luo, Xixi ; Cohen, Kenneth S. ; Gajewski, Thomas F. / Therapeutic activity of high-dose intratumoral IFN-β requires direct effect on the tumor vasculature. In: Journal of Immunology. 2014 ; Vol. 193, No. 8. pp. 4254-4260.
@article{aff0801d567440bcaa966b6e85fb8079,
title = "Therapeutic activity of high-dose intratumoral IFN-β requires direct effect on the tumor vasculature",
abstract = "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.",
author = "Spaapen, {Robbert M.} and Leung, {Michael Y.K.} and Fuertes, {Mercedes B.} and Kline, {Justin P.} and Long Zhang and Yan Zheng and Fu, {Yang Xin} and Xixi Luo and Cohen, {Kenneth S.} and Gajewski, {Thomas F.}",
year = "2014",
month = "1",
day = "1",
doi = "10.4049/jimmunol.1401109",
language = "English (US)",
volume = "193",
pages = "4254--4260",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "8",

}

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.

PY - 2014/1/1

Y1 - 2014/1/1

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.

UR - http://www.scopus.com/inward/record.url?scp=84907495019&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907495019&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1401109

DO - 10.4049/jimmunol.1401109

M3 - Article

C2 - 25217157

AN - SCOPUS:84907495019

VL - 193

SP - 4254

EP - 4260

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 8

ER -