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

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. Overall design: RNA-seq profiling of wild-type B16F10 and Pros1-deficient (BdP) syngeneic murine tumors treated with vehicle (PBS) or two rounds of cisplatin (5mg/kg, intraperitoneally, once daily for 3 days)

传统抗肿瘤疗法可诱导肿瘤细胞死亡，进而释放损伤相关分子模式（Damage Associated Molecular Patterns, DAMPs），激活先天炎症应答。矛盾的是，治疗后巨噬细胞往往会呈现促伤口愈合而非促炎的表型，进而促进肿瘤进展。本研究发现，在DAMPs释放的邻近区域，肿瘤细胞会上调Pros1的表达。肿瘤分泌的Pros1可结合巨噬细胞Mer受体，通过阻断Toll样受体（Toll Like Receptor, TLR）的信号转导，有效抑制细胞对DAMPs的应答。通过药理学手段抑制Mer受体下游的蛋白酪氨酸磷酸酶1B（Protein Tyrosine Phosphatase 1B, PTP1B）信号通路，即便存在Pros1，也可恢复巨噬细胞的促炎应答。将PTP1B抑制疗法与传统抗肿瘤疗法（如化疗或放疗）联合使用，可恢复机体对DAMPs的先天免疫应答，增强免疫浸润，并在多种治疗抵抗性临床前模型中使肿瘤生长降低40%~90%。本研究结果表明，PTP1B抑制剂可作为一种泛肿瘤适用的手段，提升部分临床最常用抗肿瘤治疗药物的疗效。实验整体设计：对经溶剂（磷酸盐缓冲液，PBS）或两轮顺铂治疗（5mg/kg，腹腔注射，每日1次，连续3天）的野生型B16F10与Pros1缺陷型（BdP）同基因小鼠肿瘤进行RNA测序（RNA-seq）转录组分析。