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Systemic inhibition of PTPN22 augments anticancer immunity
Won Jin Ho, … , Zhong-Yin Zhang, Elizabeth M. Jaffee
Won Jin Ho, … , Zhong-Yin Zhang, Elizabeth M. Jaffee
Published July 20, 2021
Citation Information: J Clin Invest. 2021;131(17):e146950. https://doi.org/10.1172/JCI146950.
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Research Article Immunology Oncology

Systemic inhibition of PTPN22 augments anticancer immunity

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Abstract

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.

Authors

Won Jin Ho, Sarah Croessmann, Jianping Lin, Zaw H. Phyo, Soren Charmsaz, Ludmila Danilova, Aditya A. Mohan, Nicole E. Gross, Fangluo Chen, Jiajun Dong, Devesh Aggarwal, Yunpeng Bai, Janey Wang, Jing He, James M. Leatherman, Mark Yarchoan, Todd D. Armstrong, Neeha Zaidi, Elana J. Fertig, Joshua C. Denny, Ben H. Park, Zhong-Yin Zhang, Elizabeth M. Jaffee

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Figure 1

PTPN22 is associated with a negative regulatory role in the immune response against cancer.

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PTPN22 is associated with a negative regulatory role in the immune respo...
(A) A volcano plot showing the results from the analysis using phenome-wide association studies (PheWAS) from the Vanderbilt BioVU database (n = 72,083). Each dot represents an association between Ptpn22 rs2476601 and a disease diagnosis. The horizontal dashed line indicates an FDR-adjusted P value of 0.05. (B) Correlations between Ptpn22 expression and immune cell types deconvolved by CIBERSORT across 11 cancer types from The Cancer Genome Atlas (TCGA) are shown as a heatmap. (C) Correlation between Ptpn22 and immune regulatory markers across 11 cancer types from TCGA are shown as a heatmap. BLCA, bladder cancer; BRCA, breast cancer; COAD, colon adenocarcinoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous cell cancer; LIHC, hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; PAAD, pancreatic ductal adenocarcinoma; PRAD, prostate adenocarcinoma; SKCM, skin melanoma.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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