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

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 4

Antitumor effects of PTPN22 inhibition are mediated by CD8+ T cells.

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Antitumor effects of PTPN22 inhibition are mediated by CD8+ T cells. (A)...
(A) Tumor growth was compared across 6 groups: WT or PTPN22-KO mice treated with isotype, anti-CD4, or anti-CD8 antibodies (n = 4–5). Representative of 2 independent runs. *P < 0.05, ***P < 0.005 by nonlinear regression. (B and C) TCR repertoires for T cells infiltrating MC38 tumors were compared for WT vs. PTPN22-KO and VEH vs. L-1 treatments by TCRseq based on Shannon’s entropy and sample clonality (n = 4–5). *P < 0.05. (D) Tumor resistance experiment with EG7 tumors: 2.5 × 105 cells were injected subcutaneously in the right hind limb, and tumor persistence was assessed on day 35. The frequency of tumors rejected in WT and PTPN22-KO mice is displayed (n = 20). (E) SIINFEKL tetramer+ CD8+ T cells in the tumor-draining lymph nodes from EG7 tumor–bearing mice were compared by flow cytometry using 1-way ANOVA followed by pairwise Tukey’s test (n = 9). *P < 0.05. (F) SIINFEKL tetramer+ CD8+ T cells from the spleens of vaccinated mice (n = 5). *P < 0.05, ***P < 0.005 by 1-way ANOVA followed by pairwise Tukey’s test. (G) Phosphorylation intensities (mean metal intensities) for each of the indicated phospho-site, stratified by the subtype of CD8+ T cells, comparing MC38 tumor–infiltrating CD8+ T cells from WT and PTPN22-KO mice (n = 5). In the box-and-whisker plots in B, C, and G, the bottom and top hinges of the boxes mark the 25th and 75th percentiles, respectively, and the lines within the boxes are medians. Whiskers represent 1.5 times the interquartile range extending from the hinges. Results of linear mixed modeling for differential analyses of the phosphorylation levels are shown as FDR-adjusted P values: *P < 0.1, ***P < 0.005. Detailed annotations of CD8+ T cell clusters are shown in Supplemental Figure 7. CM, central memory subtype; EM, effector memory subtype; Eff, effector subtype; EX, exhausted subtype (positive expression of checkpoint markers).