Pro-autoimmune allele of tyrosine phosphatase, PTPN22, enhances tumor immunity

Abstract

AbstractThe 1858C>T allele of the tyrosine phosphatase PTPN22 (causing amino acid substitution R620W in encoded protein Lyp) 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 pro-autoimmune allele has in tumor immunity is poorly defined. To interrogate the role this allele may have in the anti-tumor immune response, we used CRISPR/Cas9 to generate mice in which the ortholog of Lyp, PEP, is mutated at position 619 to produce the relevant pro-autoimmune mutation (R619W). Results of this study show that mice homozygous for this alteration (PEP-619WW) resist tumor growth as compared with wildtype mice. Consistent with these results, tumors from PEP-619WW mice have more CD45 infiltrates containing more activated CD8 T cell and CD4 T cells. Additionally, there are more cDC1 cells and less MDSCs in tumors from PEP-619WW mice. Interestingly, the tumor infiltrating PEP-619WW cDC1s have decreased PD-L1 expression compared to cDC1s from PEP-WT mice. Taken together, our data show that the pro-autoimmune allele of Ptpn22 drives a strong anti-tumor response in innate and adaptive immune cells resulting in superior control of tumors.