Targeting PTPN22 for Novel Cancer Immunotherapeutic Agents

While recent progress in cancer immunotherapy has led to revolutionary success in some cancers, most patients do not benefit from current therapies. As the majority of the existing immunotherapeutic strategies target immune check point receptors with large biologic molecules or cells, they have limited access to the tumor microenvironment, incur substantial medical expenses, and are often associated with significant immune-related adverse events. Consequently, there is a critical need to identify new targets and develop novel approaches to improve cancer immunity and benefit more patients. To that end, the pursuit of small molecule immune modulators targeting intracellular regulatory mechanisms has emerged as an increasingly attractive avenue, as they can overcome many of the challenges associated with standard immunotherapies. Protein Tyrosine Phosphatase Non-receptor type 22 (PTPN22) has been identified as a promising target for novel small molecule immunotherapeutic agents. PTPN22 is a cytosolic protein tyrosine phosphatase predominantly expressed in immune cells and functions as a negative regulator of the immune system. Consistent with its negative role in immunity, a missense C1858T single nucleotide polymorphism in PTPN22, resulting in the R620W variant, is a common risk factor for multiple autoimmune diseases. The PTPN22 R620W variant behaves like a loss-of-function mutant and portends a lower likelihood of cancer in patients and responds significantly better to checkpoint inhibitor immunotherapy. Additionally, mice deficient in PTPN22 or mice expressing the murine ortholog variant R619W or the catalytically inactive C227S mutant exhibit robust anti-tumor immunity against syngeneic tumor models. Thus, blocking PTPN22 activity represents an exciting immunotherapeutic strategy, as PTPN22 inhibition would be predicted to unleash host immunity against tumor cells. We hypothesize that potent and selective PTPN22 inhibitors enable direct pharmacologic validation of PTPN22 as a translatable drug target and offer a solid starting point for the development of new immunotherapeutic agents. To that end, we have identified hit compounds that inhibit PTPN22 with an IC50 of 0.49-1.4 ìM and >7-14-fold selectivity for PTPN22 against a large panel of protein tyrosine phosphatases. In addition, these inhibitors efficaciously enhance T cell activation and signaling. The overall goal of this proposal is to employ a multifaceted and integrated approach to optimize the existing hit molecules into preclinical leads to further assess the therapeutic potential of targeting PTPN22. Importantly, this proposal will benchmark the in vivo efficacy of optimized inhibitors, a critical step for translation that can be only achieved by controlled experiments in immunocompetent mouse models of varying immunotherapy sensitivity. Successful completion of this project will create a solid foundation upon which novel PTPN22-based immunotherapy can be developed. Moreover, success of this project will also galvanize the development of therapeutics targeting other members of the protein tyrosine phosphatase family, ultimately impacting broadly on human health. Project Number: 1R01CA300086-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Zhong-Yin Zhang (+1 co-PI) | Institution: PURDUE UNIVERSITY, WEST LAFAYETTE, IN | Award Amount: $593,249 | Activity Code: R01 | Study Section: Drug Discovery and Molecular Pharmacology C Study Section[DMPC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11297010