Proautoimmune Allele of Tyrosine Phosphatase, PTPN22, Enhances Tumor Immunity

Abstract

The 1858C>T allele of the tyrosine phosphatase PTPN22 (causing amino acid substitution R620W in encoded protein lymphoid tyrosine phosphatase) is present in 5–10% of the North American population and is strongly associated with numerous autoimmune diseases. Although much research has been done to define how this allele potentiates autoimmunity, the influence PTPN22 and its proautoimmune allele have in tumor immunity is poorly defined. To interrogate the role this allele may have in the antitumor immune response, we used CRISPR/Cas9 to generate mice in which the ortholog of lymphoid tyrosine phosphatase, PEST domain–enriched protein (PEP), is mutated at position 619 to produce the relevant proautoimmune mutation (R619W). Results of this study show that mice homozygous for this alteration (PEP-619WW) resist tumor growth as compared with wild-type mice. Consistent with these results, tumors from PEP-619WW mice have more CD45 infiltrates containing more activated CD8 T cells and CD4 T cells. In addition, there are more conventional dendritic cell type 1 (cDC1) cells and fewer myeloid-derived suppressor cells in tumors from PEP-619WW mice. Interestingly, the tumor-infiltrating PEP-619WW cDC1 cells have decreased PD-L1 expression compared with cDC1 cells from PEP-wild-type mice. Taken together, our data show that the proautoimmune allele of Ptpn22 drives a strong antitumor response in innate and adaptive immune cells resulting in superior control of tumors.