The Autoimmune-Associated PTPN22 Variant Promotes Anti-Tumor Immunity in Melanoma 2310217

Abstract

Abstract Introduction The autoimmune risk allele of PTPN22, 1858C>T, reduces melanoma risk, but the underlying mechanisms are unclear. In humans and mice, PTPN22 encodes the immune regulatory protein Lyp (PEP in mice), expressed almost exclusively in immune cells. We previously showed that mice expressing the equivalent 1858C>T allele, PEP-R619W mice, exhibit reduced B16-OVA melanoma burden. Notably, PEP-R619W mice had more intratumoral CD8 T cells and type I dendritic cells. However, it is unknown if other immune cells shaping the tumor microenvironment, such as CD4 T cells and macrophages, are altered in PEP-R619W tumor-bearing mice. It is also unclear if PEP-R619W immune cells still delay B16-OVA tumor growth in the presence of wildtype (PEP-WT) immune cells. Methods We immunophenotyped the intratumoral immune response of PEP-WT and PEP-R619W mice using single-cell RNA sequencing and flow cytometry. To interrogate how PEP-R619W affects specific immune cell interactions, we generated and used co-culture and tri-culture systems of CD4 T cells, bone marrow-derived macrophages, and B16-OVA cells. Next, we investigated if PEP-R619W immune cells could reduce B16-OVA tumor growth in the presence of PEP-WT cells using PEP-WT: PEP-R619W bone marrow chimeric (BMC) mice. Results PEP-R619W mice have a more pro-inflammatory macrophage population within the tumor. Yet, PEP-R619W macrophages do not activate CD4 T cells differently from PEP-WT macrophages in the absence of tumor cells. Intriguingly, in the presence of tumor cells, PEP-R619W CD4 T cells were more activated and more proliferative- suggesting that PEP-R619W may impact tumor-immune cell interactions. Finally, BMC mice, which have both PEP-WT and PEP-R619W expressing cells had delayed tumor growth compared to PEP-WT mice. Conclusion This study shows that PEP-R619W shifts the macrophage landscape within the tumor and that PEP-R619W may impact tumor-immune cell interactions. Further, we show PEP-R619W cells can still reduce tumor burden when PEP-WT cells are present. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)