PDF(Pubmed)
Abstract：
Despite the central role of T cells in tumor immunity, attempts to harness their cytotoxic capacity as a therapy have met limited efficacy, partially as a result of the suppressive microenvironment which limits their migration and activation. In contrast, myeloid cells massively infiltrate tumors and are well adapted to survive these harsh conditions. While they are equipped with cell-killing abilities, they often adopt an immunosuppressive phenotype upon migration to tumors. Therefore, the questions of how to modify their activation programming against cancer, and what signaling cascades should be activated in myeloid cells to elicit their cytotoxicity have remained unclear. Here, we found that activation of IgM-induced signaling in murine myeloid cells results in secretion of lytic granules and massive tumor cell death. These findings open venues for designing novel immunotherapy by equipping monocytes with chimeric receptors that target tumor antigens and consequently, signal through IgM receptor. Nonetheless, we found that myeloid cells do not express the antibody-derived portion used to recognize the tumor antigen due to the induction of an ER stress response. To overcome this limitation, we designed chimeric receptors that are based on the high-affinity FcγRI for IgG. Incubation of macrophages expressing these receptors along with tumor-binding IgG induced massive tumor cell killing and secretion of reactive oxygen species and Granzyme B. Overall, this work highlights the challenges involved in genetically reprogramming the signaling in myeloid cells and provides a framework for endowing myeloid cells with antigen-specific cytotoxicity.
摘要：
尽管T细胞在肿瘤免疫中起着核心作用，试图利用它们的细胞毒性能力作为一种治疗方法，效果有限，部分是由于抑制微环境限制了它们的迁移和激活。相比之下,骨髓细胞大量浸润肿瘤，并且很好地适应了这些苛刻的条件。虽然它们具备杀伤细胞的能力,它们通常在迁移到肿瘤后采用免疫抑制表型。因此,如何修改他们针对癌症的激活程序，以及在骨髓细胞中应该激活哪些信号级联以引起其细胞毒性仍不清楚。这里,我们发现在小鼠骨髓细胞中IgM诱导的信号激活导致溶解颗粒的分泌和大量肿瘤细胞死亡。这些发现为设计新型免疫疗法开辟了场所，通过为单核细胞配备靶向肿瘤抗原的嵌合受体，信号通过IgM受体。尽管如此，我们发现,由于ER应激反应的诱导,骨髓细胞不表达用于识别肿瘤抗原的抗体衍生部分.为了克服这个限制,我们设计了基于IgG高亲和力FcγRI的嵌合受体。表达这些受体的巨噬细胞与肿瘤结合IgG一起孵育诱导大量肿瘤细胞杀伤和分泌活性氧和颗粒酶B。这项工作突出了在基因重编程髓样细胞信号中涉及的挑战,并为赋予髓样细胞抗原特异性细胞毒性提供了框架.
