CD73 expression on effector T cells sustained by TGF-β facilitates tumor resistance to anti-4-1BB/CD137 therapy

Siqi Chen; Jie Fan; Minghui Zhang; Lei Qin; Donye Dominguez; Alan Long; Gaoxiang Wang; Renqiang Ma; Huabin Li; Yi Zhang; Deyu Fang; Jeffrey Sosman; Bin Zhang

doi:10.1038/s41467-018-08123-8

CD73 expression on effector T cells sustained by TGF-β facilitates tumor resistance to anti-4-1BB/CD137 therapy

Siqi Chen, Jie Fan, Minghui Zhang, Lei Qin, Donye Dominguez, Alan Long, Gaoxiang Wang, Renqiang Ma, Huabin Li, Yi Zhang, Deyu Fang, Jeffrey Sosman, Bin Zhang^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

52 Scopus citations

Abstract

Agonist antibodies (Ab) directed against costimulatory molecules on the surface of antigen-primed T cells are in various stages of pre-clinical and clinical trials, albeit with limited therapeutic benefit as single agents. The underlying mechanisms of action remain incompletely understood. Here, we demonstrate an inhibitory role of ecto-enzyme CD73 for agonistic anti-4-1BB/CD137 Ab therapy. In particular, anti-4-1BB treatment preferentially drives CD73 ⁻ effector T cell response for tumor inhibition. Anti-CD73 neutralizing Ab further improves anti-4-1BB therapy associated with enhanced anti-tumor T cell immunity. However, the TGF-β-rich tumor milieu confers resistance to anti-4-1BB therapy by sustaining CD73 expression primarily on infiltrating CD8 ⁺ T cells across several tumor models. TGF-β blockade results in downregulation of CD73 expression on infiltrating T cells and sensitizes resistant tumors to agonistic anti-4-1BB therapy. Thus, our findings identify a mechanism of action for more effective clinical targeting of 4-1BB or likely other costimulatory molecules.

Original language	English (US)
Article number	150
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-08123-8
State	Published - Dec 1 2019
Externally published	Yes

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

Access to Document

10.1038/s41467-018-08123-8

Cite this

@article{320702cbd1c74e8a927e7464179e45ad,

title = "CD73 expression on effector T cells sustained by TGF-β facilitates tumor resistance to anti-4-1BB/CD137 therapy",

abstract = " Agonist antibodies (Ab) directed against costimulatory molecules on the surface of antigen-primed T cells are in various stages of pre-clinical and clinical trials, albeit with limited therapeutic benefit as single agents. The underlying mechanisms of action remain incompletely understood. Here, we demonstrate an inhibitory role of ecto-enzyme CD73 for agonistic anti-4-1BB/CD137 Ab therapy. In particular, anti-4-1BB treatment preferentially drives CD73 − effector T cell response for tumor inhibition. Anti-CD73 neutralizing Ab further improves anti-4-1BB therapy associated with enhanced anti-tumor T cell immunity. However, the TGF-β-rich tumor milieu confers resistance to anti-4-1BB therapy by sustaining CD73 expression primarily on infiltrating CD8 + T cells across several tumor models. TGF-β blockade results in downregulation of CD73 expression on infiltrating T cells and sensitizes resistant tumors to agonistic anti-4-1BB therapy. Thus, our findings identify a mechanism of action for more effective clinical targeting of 4-1BB or likely other costimulatory molecules.",

author = "Siqi Chen and Jie Fan and Minghui Zhang and Lei Qin and Donye Dominguez and Alan Long and Gaoxiang Wang and Renqiang Ma and Huabin Li and Yi Zhang and Deyu Fang and Jeffrey Sosman and Bin Zhang",

note = "Funding Information: This research was in part supported by National Institutes of Health grant CA149669, CA208354, and CA222963, Melanoma Research Alliance Pilot Award, the Marsha Rivkin Center for Ovarian Cancer Research Pilot Award, CBC HTS Supplemental Grant to B.Z., Northwestern University RHLCCC Flow Cytometry Facility, a Cancer Center Support Grant (NCI CA060553), the Robert H. Lurie Comprehensive Cancer Center and the National Natural Science Foundation of China (No. 81725004) to H.L. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-018-08123-8",

language = "English (US)",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - CD73 expression on effector T cells sustained by TGF-β facilitates tumor resistance to anti-4-1BB/CD137 therapy

AU - Chen, Siqi

AU - Fan, Jie

AU - Zhang, Minghui

AU - Qin, Lei

AU - Dominguez, Donye

AU - Long, Alan

AU - Wang, Gaoxiang

AU - Ma, Renqiang

AU - Li, Huabin

AU - Zhang, Yi

AU - Fang, Deyu

AU - Sosman, Jeffrey

AU - Zhang, Bin

N1 - Funding Information: This research was in part supported by National Institutes of Health grant CA149669, CA208354, and CA222963, Melanoma Research Alliance Pilot Award, the Marsha Rivkin Center for Ovarian Cancer Research Pilot Award, CBC HTS Supplemental Grant to B.Z., Northwestern University RHLCCC Flow Cytometry Facility, a Cancer Center Support Grant (NCI CA060553), the Robert H. Lurie Comprehensive Cancer Center and the National Natural Science Foundation of China (No. 81725004) to H.L. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Agonist antibodies (Ab) directed against costimulatory molecules on the surface of antigen-primed T cells are in various stages of pre-clinical and clinical trials, albeit with limited therapeutic benefit as single agents. The underlying mechanisms of action remain incompletely understood. Here, we demonstrate an inhibitory role of ecto-enzyme CD73 for agonistic anti-4-1BB/CD137 Ab therapy. In particular, anti-4-1BB treatment preferentially drives CD73 − effector T cell response for tumor inhibition. Anti-CD73 neutralizing Ab further improves anti-4-1BB therapy associated with enhanced anti-tumor T cell immunity. However, the TGF-β-rich tumor milieu confers resistance to anti-4-1BB therapy by sustaining CD73 expression primarily on infiltrating CD8 + T cells across several tumor models. TGF-β blockade results in downregulation of CD73 expression on infiltrating T cells and sensitizes resistant tumors to agonistic anti-4-1BB therapy. Thus, our findings identify a mechanism of action for more effective clinical targeting of 4-1BB or likely other costimulatory molecules.

AB - Agonist antibodies (Ab) directed against costimulatory molecules on the surface of antigen-primed T cells are in various stages of pre-clinical and clinical trials, albeit with limited therapeutic benefit as single agents. The underlying mechanisms of action remain incompletely understood. Here, we demonstrate an inhibitory role of ecto-enzyme CD73 for agonistic anti-4-1BB/CD137 Ab therapy. In particular, anti-4-1BB treatment preferentially drives CD73 − effector T cell response for tumor inhibition. Anti-CD73 neutralizing Ab further improves anti-4-1BB therapy associated with enhanced anti-tumor T cell immunity. However, the TGF-β-rich tumor milieu confers resistance to anti-4-1BB therapy by sustaining CD73 expression primarily on infiltrating CD8 + T cells across several tumor models. TGF-β blockade results in downregulation of CD73 expression on infiltrating T cells and sensitizes resistant tumors to agonistic anti-4-1BB therapy. Thus, our findings identify a mechanism of action for more effective clinical targeting of 4-1BB or likely other costimulatory molecules.

UR - http://www.scopus.com/inward/record.url?scp=85059903022&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059903022&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-08123-8

DO - 10.1038/s41467-018-08123-8

M3 - Article

C2 - 30635578

AN - SCOPUS:85059903022

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 150

ER -

CD73 expression on effector T cells sustained by TGF-β facilitates tumor resistance to anti-4-1BB/CD137 therapy

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this