The HIV latency reversing agent HODHBt inhibits the phosphatases PTPN1 and PTPN2.

Nonreceptor tyrosine phosphatases (NTPs) play an important role regulating protein phosphorylation and have been proposed as attractive therapeutic targets for cancer and metabolic diseases. We have previously identified that 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one (HODHBt) enhanced STAT activation upon cytokine stimulation leading to increased reactivation of latent HIV and effector functions of NK and CD8 T cells. Here, we demonstrated that HODHBt interacts with and inhibits the NTPs PTPN1 and PTPN2 through a mixed inhibition mechanism. We also confirmed that PTPN1 and PTPN2 specifically control the phosphorylation of different STATs. The small molecule ABBV-CLS-484 (AC-484) is an active site inhibitor of PTPN1 and PTPN2 currently in clinical trials for advanced solid tumors. We compared AC-484 and HODHBt and found similar effects on STAT5 and immune activation albeit with different mechanisms of action leading to varying effects on latency reversal. Our studies provide the first specific evidence that enhancing STAT phosphorylation via inhibition of PTPN1 and PTPN2 is an effective tool against HIV.

Photothermal Prussian blue nanoparticles generate potent multi-targeted tumor-specific T cells as an adoptive cell therapy.

Prussian blue nanoparticle-based photothermal therapy (PBNP-PTT) is an effective tumor treatment capable of eliciting an antitumor immune response. Motivated by the ability of PBNP-PTT to potentiate endogenous immune responses, we recently demonstrated that PBNP-PTT could be used ex vivo to generate tumor-specific T cells against glioblastoma (GBM) cell lines as an adoptive T cell therapy (ATCT). In this study, we further developed this promising T cell development platform. First, we assessed the phenotype and function of T cells generated using PBNP-PTT. We observed that PBNP-PTT facilitated CD8+ T cell expansion from healthy donor PBMCs that secreted IFNγ and TNFα and upregulated CD107a in response to engagement with target U87 cells, suggesting specific antitumor T cell activation and degranulation. Further, CD8+ effector and effector memory T cell populations significantly expanded after co-culture with U87 cells, consistent with tumor-specific effector responses. In orthotopically implanted U87 GBM tumors in vivo, PBNP-PTT-derived T cells effectively reduced U87 tumor growth and generated long-term survival in >80% of tumor-bearing mice by Day 100, compared to 0% of mice treated with PBS, non-specific T cells, or T cells expanded from lysed U87 cells, demonstrating an enhanced antitumor efficacy of this ATCT platform. Finally, we tested the generalizability of our approach by generating T cells targeting medulloblastoma (D556), breast cancer (MDA-MB-231), neuroblastoma (SH-SY5Y), and acute monocytic leukemia (THP-1) cell lines. The resulting T cells secreted IFNγ and exerted increased tumor-specific cytolytic function relative to controls, demonstrating the versatility of PBNP-PTT in generating tumor-specific T cells for ATCT.