Systemic inhibition of PTPN22 augments anticancer immunity

被引:25
|
作者
Ho, Won Jin [1 ]
Croessmann, Sarah [2 ]
Lin, Jianping [3 ,4 ]
Phyo, Zaw H. [1 ]
Charmsaz, Soren [1 ]
Danilova, Ludmila [1 ]
Mohan, Aditya A. [1 ]
Gross, Nicole E. [1 ]
Chen, Fangluo [1 ]
Dong, Jiajun [3 ,4 ]
Aggarwal, Devesh [3 ,4 ]
Bai, Yunpeng [3 ,4 ]
Wang, Janey [5 ]
He, Jing [5 ]
Leatherman, James M. [1 ]
Yarchoan, Mark [1 ]
Armstrong, Todd D. [1 ]
Zaidi, Neeha [1 ]
Fertig, Elana J. [1 ]
Denny, Joshua C. [2 ,5 ,6 ,7 ]
Park, Ben H. [2 ]
Zhang, Zhong-Yin [3 ,4 ]
Jaffee, Elizabeth M. [1 ]
机构
[1] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA
[2] Vanderbilt Univ, Dept Med, Med Ctr, Nashville, TN USA
[3] Purdue Univ, Dept Chem, Dept Med Chem & Mol Pharmacol, Ctr Canc Res, W Lafayette, IN 47907 USA
[4] Purdue Univ, Inst Drug Discovery, W Lafayette, IN 47907 USA
[5] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN USA
[6] All US Res Program, Bethesda, MD USA
[7] NHGRI, NIH, Bethesda, MD 20892 USA
来源
JOURNAL OF CLINICAL INVESTIGATION | 2021年 / 131卷 / 17期
关键词
TYROSINE-PHOSPHATASE PTPN22; T-CELLS; INTERFERON-GAMMA; RESPONSES; VARIANT; IDENTIFICATION; AUTOIMMUNITY; POLYMORPHISM; ASSOCIATION; CYTOMETRY;
D O I
10.1172/JCI146950
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Both epidemiologic and cellular studies in the context of autoimmune diseases have established that protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is a key regulator of T cell receptor (TCR) signaling. However, its mechanism of action in tumors and its translatability as a target for cancer immunotherapy have not been established. Here, we show that a germline variant of PTPN22, rs2476601, portended a lower likelihood of cancer in patients. PTPN22 expression was also associated with markers of immune regulation in multiple cancer types. In mice, lack of PTPN22 augmented antitumor activity with greater infiltration and activation of macrophages, natural killer (NK) cells, and T cells. Notably, we generated a small molecule inhibitor of PTPN22, named L-1, that phenocopied the antitumor effects seen in genotypic PTPN22 knockout. PTPN22 inhibition promoted activation of CD8(+) T cells and macrophage subpopulations toward MHC-II-expressing M1-like phenotypes, both of which were necessary for successful antitumor efficacy. Increased PD-1/PD-L1 axis expression in the setting of PTPN22 inhibition could be further leveraged with PD-1 inhibition to augment antitumor effects. Similarly, cancer patients with the rs2476601 variant responded significantly better to checkpoint inhibitor immunotherapy. Our findings suggest that PTPN22 is a druggable systemic target for cancer immunotherapy.
引用
收藏
页数:15
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