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Ptp1b inhibition improves the macrophage anti-tumor immune response and the efficacy of chemo- and radiotherapy.

ABSTRACT: Traditional anti-cancer therapies induce tumor cell death and subsequent release of Damage Associated Molecular Patterns (DAMPs) that activate the innate inflammatory response. Paradoxically, after treatment macrophages often adopt a pro-wound healing, rather than pro-inflammatory, phenotype and contribute to cancer progression. We found that in areas proximal to DAMP release, tumor cells upregulate the expression of Pros1. Tumor-secreted Pros1 binds to the macrophage Mer receptor, effectively limiting responsiveness to DAMPs by preventing Toll Like Receptor (TLR) signal transduction. Pharmacologically inhibiting PTP1b signaling downstream of Mer rescues the pro-inflammatory response even in the presence of Pros1. Combining PTP inhibition with traditional therapeutics, like chemo- or radiotherapy, rescues the innate immune response to DAMPs, increases immune infiltration, and causes 40-90% reductions in tumor growth in multiple treatment refractory preclinical models. Our findings suggest a novel use for PTP1b inhibitors as a tumor agnostic means of improving the efficacy of some of the most widely used anti-cancer therapeutic agents.

ORGANISM(S): Mus musculus

PROVIDER: GSE283503 | GEO | 2025/01/02

REPOSITORIES: GEO

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Project description:The tumor microenvironment (TME) typically includes hypoxic regions. Hypoxic cancer cells are resistant to many anti-neoplastic therapies and can seed recurrence; consequently, understanding how they survive could yield new therapeutic strategies. In response to decreasing oxygen, cells are known to successively activate hypoxia-inducible factor 1-alpha (HIF1alpha), endoplasmic reticulum (ER) stress, and AMP-dependent protein kinase (AMPK). We previously identified an additional pathway in which the protein-tyrosine phosphatase PTP1B (encoded by PTPN1) prevents the death of HER2+ breast cancer cells exposed to severe hypoxia (O2<1%) by inhibiting RNF213, a large (~600 kDa) E3 ubiquitin ligase containing two functional AAA-ATPase domains and two ubiquitin ligase domains (RING and RZ) that also is implicated in Moyamoya disease (MMD), lipotoxicity, and innate immunity. These findings provided a potential explanation for earlier observations that Ptpn1-/- mice are resistant to Neu (rodent HER2)-induced breast cancer, but how PTP1B regulates RNF213, the identity(ies) of RNF213 targets, the mechanism of cell death, and the relevance to other RNF213 actions remained unclear. Via proximity-based proteomics, we identified the CYLD-SPATA2 complex, a major negative regulator of NF-kappaB activation, as an RNF213 substrate critical for hypoxia-induced cell death. Here we show that PTP1B and ABL1/2 reciprocally control the phosphorylation of RNF213 on Tyrosine-1275. Phosphorylation of this site promotes RNF213 oligomerization, resulting in RZ domain activation, LUBAC complex-dependent ubiquitylation and degradation of the CYLD/SPATA2 deubiquitinase complex, and NF-kappaB activation. NF-kappaB induces NLRP3 inflammasome priming, and concomitant hypoxia-induced ER stress triggers inflammasome activation, resulting in pyroptotic cell death. Mutagenesis experiments show that the RNF213 RING negatively regulates the RZ domain, and RING domain mutants, including those associated with MMD, catalyze LUBAC-independent CYLD/SPATA2 degradation. Our results identify a novel PTP1B/RNF213/CYLD/SPATA2 pathway responsible for the pyroptotic death of hypoxic tumor cells, reveal new insights into RNF213 regulation, and have potentially important implications for the pathogenesis of MMD, atherosclerosis, and inflammatory and auto-immune disorders. The mass spectrometry raw files for the phosphorylation identification and proximity labeling results are included here.

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Ptp1b inhibition improves the macrophage anti-tumor immune response and the efficacy of chemo- and radiotherapy.

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