Revolution Medicines, Inc., Redwood City, CA, United States.
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, United States.
Front Immunol. 2020 Sep 29;11:576310. doi: 10.3389/fimmu.2020.576310. eCollection 2020.
Shp1, encoded by the gene , is a protein tyrosine phosphatase that transduces inhibitory signals downstream of immunoreceptors in many immune cell types. Blocking Shp1 activity represents an exciting potential immunotherapeutic strategy for the treatment of cancer, as Shp1 inhibition would be predicted to unleash both innate and adaptive immunity against tumor cells. Antibodies blocking the interaction between CD47 on tumor cells and SIRPα on macrophages enhance macrophage phagocytosis, show efficacy in preclinical tumor models, and are being evaluated in the clinic. Here we found that Shp1 bound to phosphorylated peptide sequences derived from SIRPα and transduced the anti-phagocytic signal, as Shp1 loss in mouse bone marrow-derived macrophages increased phagocytosis of tumor cells . We also generated a novel mouse model to evaluate the impact of global, inducible deletion on anti-tumor immunity. We found that inducible Shp1 loss drove an inflammatory disease in mice that was phenotypically similar to that seen when is knocked out from birth. This indicates that acute perturbation of Shp1 could drive hyperactivation of immune cells, which could be therapeutically beneficial, though at the risk of potential toxicity. In this model, we found that Shp1 loss led to robust anti-tumor immunity against two immune-rich syngeneic tumor models that are moderately inflamed though not responsive to checkpoint inhibitors, MC38 and E0771. Shp1 loss did not promote anti-tumor activity in the non-inflamed B16F10 model. The observed activity in MC38 and E0771 tumors was likely due to effects of both innate and adaptive immune cells. Following Shp1 deletion, we observed increases in intratumoral myeloid cells in both models, which was more striking in E0771 tumors. E0771 tumors also contained an increased ratio of effector to regulatory T cells following Shp1 loss. This was not observed for MC38 tumors, though we did find increased levels of IFNγ, a cytokine produced by effector T cells, in these tumors. Overall, our preclinical data suggested that targeting Shp1 may be an attractive therapeutic strategy for boosting the immune response to cancer via a mechanism involving both innate and adaptive leukocytes.
Shp1 由基因编码，是一种蛋白酪氨酸磷酸酶，可在多种免疫细胞类型中传递免疫受体下游的抑制信号。阻断 Shp1 活性代表了一种令人兴奋的潜在免疫治疗策略，可用于治疗癌症，因为预计 Shp1 抑制会释放针对肿瘤细胞的先天和适应性免疫。阻断肿瘤细胞上的 CD47 与巨噬细胞上的 SIRPα 之间相互作用的抗体增强了巨噬细胞的吞噬作用，在临床前肿瘤模型中显示出疗效，并正在临床中进行评估。在这里，我们发现 Shp1 与源自 SIRPα 的磷酸化肽序列结合并传递抗吞噬信号，因为小鼠骨髓来源的巨噬细胞中 Shp1 的缺失增加了肿瘤细胞的吞噬作用。我们还生成了一种新型小鼠模型来评估全局诱导性缺失对抗肿瘤免疫的影响。我们发现，诱导性 Shp1 缺失会导致小鼠发生炎症性疾病，其表型与从出生时敲除时相似。这表明 Shp1 的急性扰动可能会驱动免疫细胞的过度激活，尽管有潜在毒性的风险，但这可能具有治疗益处。在该模型中，我们发现 Shp1 缺失导致对两种免疫丰富的同源肿瘤模型（MC38 和 E0771）产生强烈的抗肿瘤免疫，这两种模型适度发炎，但对检查点抑制剂无反应。Shp1 缺失并未促进非发炎的 B16F10 模型中的抗肿瘤活性。在 MC38 和 E0771 肿瘤中观察到的活性可能归因于先天和适应性免疫细胞的作用。在 Shp1 缺失后，我们观察到两种模型中的肿瘤内髓样细胞增加，在 E0771 肿瘤中更为明显。E0771 肿瘤中效应 T 细胞与调节性 T 细胞的比例也随着 Shp1 缺失而增加。在 MC38 肿瘤中没有观察到这种情况，尽管我们确实发现这些肿瘤中效应 T 细胞产生的细胞因子 IFNγ水平升高。总体而言，我们的临床前数据表明，通过涉及先天和适应性白细胞的机制，靶向 Shp1 可能是一种有吸引力的治疗策略，可用于增强对癌症的免疫反应。
