Abstract 6407: PTPN22-based immunotherapy yields near-complete response against PDAC via multi-pronged immune modulation

Abstract Background: The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) has few cytotoxic T cells and a predominance of immunosuppressive cells, constraining its response to checkpoint inhibitors targeting PD-1/PD-L1 and CTLA4. We recently observed that targeting protein tyrosine phosphatase non-receptor type 22 (PTPN22), a negative immune regulator, reduces tumor growth by ∼80% in an immunotherapy-resistant model of PDAC when combined with TNFRSF costimulators 41BB or OX40. These observations prompted the interrogation of the interplay between PTPN22 and TNFRSF pathways, both in T cells and myeloid cells, to determine how immunosuppressive barriers are overcome. Methods: To evaluate the effects of genetic abrogation of PTPN22, mice constitutive or myeloid-specific conditional knock out (KO) of PTPN22 were inoculated with syngeneic KPCY 6419c5 or 6422c1 cells. For pharmacologic targeting of PTPN22, we employed our small molecule PTPN22 inhibitor, L1. To determine clinical relevance, we curated and analyzed the immune profiles of patients who are heterozygous for the dysfunctional PTPN22 SNP R620W (and matched wildtype (WT) controls) undergoing checkpoint immunotherapy using CyTOF. Results: We discovered that OX40 costimulation led to TRAF3 degradation, resulting in PTPN22 translocation from the cytosol to the membrane, likely facilitating further inhibition of T cell receptor activation. Deep profiling of tumors treated with anti-PD1 and OX40 agonism upon PTPN22 abrogation revealed that intratumoral T cell expansion was driven via promotion of CD4+ helper T cell function with significant upregulation of IFN-γ, TNF-α, and IFN-α pathways. Efficacy was reproduced with a 41BB agonist and validated in orthotopic PDAC tumor models and with administration of L1. Consistent with these preclinical findings, cancer patients with the PTPN22 R620W allele undergoing immunotherapy exhibited significantly increased OX40 and PD1 expression on T cells compared to WT, highlighting the co-regulation of these immunomodulatory pathways. Conclusion: Abrogation of PTPN22 enhances PDAC immunotherapy efficacy by significantly reducing tumor burden through increasing T cell infiltration when combined with anti-PD1 and TNFRSF costimulators (OX40 or 41BB). This approach promotes CD4+ T cell activation and upregulates key inflammatory pathways. Moreover, patients heterozygous for the PTPN22 R620W allele undergoing immunotherapy showed elevated OX40 and PD1 expression on T cells underscoring the translatability of our pre-clinical findings. Citation Format: Soren Charmsaz, Nicole E. Gross, George W. Apostol, Jae W. Lee, Jianping Lin, Alexei G. Hernandez, Erin M. Coyne, Sarah M. Shin, Courtney Cannon, Xuan Yuan, James M. Leatherman, Daniel J. Zabransky, Mark Yarchoan, Zhong-Yin Zhang, Elizabeth M. Jaffee, Won Jin Ho. PTPN22-based immunotherapy yields near-complete response against PDAC via multi-pronged immune modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6407.