Abstract B003: Validating PTPN22 as a cancer-agnostic immunotherapeutic target
Authors: Babu Jayalaxmi Suresh , Charmsaz Soren , Gross Nicole E , Hernandez Alexei G , Cannon Courtney D , Yuan Xuan , Lin Jianping , Zhang Zhong-Yin , Jaffee Elizabeth M , Ho Won Jin 
Published: October 2024

Abstract
Background: Immunotherapies have shown remarkable success in cancer treatment. However, diverse tumor-specific immunosuppressive mechanisms dampen response rates highlighting the need for novel immunotherapeutic targets. Protein Tyrosine Phosphatase Non-Receptor Type 22 (PTPN22) is a phosphatase specific to hematopoietic cells that negatively regulates immune responses. For example, it functions as an early break on T cell activation by dephosphorylating tyrosine residues on Lck and ZAP70 in the T cell receptor signaling cascade. We previously demonstrated that PTPN22 abrogation can enhance antitumor efficacy against immunogenic MC38 tumors. However, it is unclear whether PTPN22 can serve as an immunotherapeutic target in more immune-resistant cancer types. Here, we evaluate the role of PTPN22 in antitumor immunity across tumor models of varying immunogenicity. Methods: We utilized tumor mouse models of varying immunogenicity ranging from the immunogenic lung model CMT167, PD1-responsive and resistant models of hepatocellular carcinoma (HCC) (Hep53.4 and RIL175, respectively), to immune-restricted triple negative breast cancer (TNBC) models (E0771.LMB and 4T1) and highly immunotherapy-resistant pancreatic ductal adenocarcinoma (PDAC) model KPCY6419c5. In addition to genetic abrogation, we tested the antitumor efficacy of pharmacologic inhibition of PTPN22 using L-1, a small molecule inhibitor of PTPN22 we previously developed. Tumors were harvested for tumor microenvironment (TME) analysis using high-parameter suspension and imaging mass cytometry (CyTOF and IMC, respectively). Results: Abrogation of PTPN22 alone or in combination with other immunomodulatory agents led to a substantial reduction in tumor growth as expected in the immunogenic models, CMT167, Hep53.4, but also in the relatively immunosuppressed models, RIL175, E0771.LMB, 4T1, and KPCY 6419c5. Analysis of tumor-infiltrating immune cells revealed an increased infiltration of CD3+ T cells within multiple models upon PTPN22 abrogation. T cell subsets also exhibited increased expression of Granzyme B, PD-1, and co-stimulatory molecules such as CD40, 4-1BB, ICOS indicating improved activation. Conclusions: Collectively, our results show that abrogation of PTPN22 yields improved anti-tumor efficacy in a range of tumor models. Additionally, PTPN22 inhibition functionally remodels T cell subsets by enhancing their activation state within the tumors in the context of varying immunogenicity. Moreover, the reproducibility of anti-tumor efficacy using L-1 suggests the translatability of targeting PTPN22 as an attractive immunotherapeutic strategy. Further work to understand how targeting PTPN22 alters the different immune cell subsets within the distinct tissue environments is warranted.
Citation Format: Jayalaxmi Suresh Babu, Soren Charmsaz, Nicole E Gross, Alexei G Hernandez, Courtney D Cannon, Xuan Yuan, Jianping Lin, Zhong-Yin Zhang, Elizabeth M Jaffee, Won Jin Ho. Validating PTPN22 as a cancer-agnostic immunotherapeutic target [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B003.