Tumor immunity is enhanced in mice expressing the pro-autoimmune allele of tyrosine phosphatase Ptpn22, but not in Ptpn22 knock-out mice

Abstract

Abstract The 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 has during 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 (PEP-619WW) or lack Ptpn22 expression (PEP-null). Using the B16 and other tumor models, we tested the hypothesis that pleiotropic effects of the PTPN22 pro-autoimmune allele enhances tumor immunity. Results of this study show that PEP-619WW mice, but not PEP-null mice, 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, more cDC1 cells, and less MDSCs than WT animals. Interestingly, the tumor infiltrating PEP-619WW cDC1s have lower PD-L1 expression compared to cDC1s from PEP-WT mice. Furthermore, using single-cell RNA sequencing we show that intra-tumoral myeloid cells from PEP-619WW mice have a more cytokine responsive transcriptional signature compared to PEP-WT cells. Our results suggest that a pro-autoimmune allele can be beneficial by promoting a strong anti-tumor immune response and may have a protective effect in this disease. Also, these data highlight an important difference between the PEP-null and PEP-619WW murine models during the tumor response. Supported by grants from NIH (UO1 AI130842 and T32 AI007354 27).