T Cell Therapeutics Research Labs, Cellular Immunotherapy Center, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
Department of Biology and Bioengineering, California Institute of Technology, Pasadena, California.
Cancer Discov. 2021 Sep;11(9):2248-2265. doi: 10.1158/2159-8290.CD-20-1661. Epub 2021 Apr 9.
Chimeric antigen receptor (CAR) T cells mediate potent antigen-specific antitumor activity; however, their indirect effects on the endogenous immune system are not well characterized. Remarkably, we demonstrate that CAR T-cell treatment of mouse syngeneic glioblastoma (GBM) activates intratumoral myeloid cells and induces endogenous T-cell memory responses coupled with feed-forward propagation of CAR T-cell responses. IFNγ production by CAR T cells and IFNγ responsiveness of host immune cells are critical for tumor immune landscape remodeling to promote a more activated and less suppressive tumor microenvironment. The clinical relevance of these observations is supported by studies showing that human IL13Rα2-CAR T cells activate patient-derived endogenous T cells and monocytes/macrophages through IFNγ signaling and induce the generation of tumor-specific T-cell responses in a responding patient with GBM. These studies establish that CAR T-cell therapy has the potential to shape the tumor microenvironment, creating a context permissible for eliciting endogenous antitumor immunity. SIGNIFICANCE: Our findings highlight the critical role of IFNγ signaling for a productive CAR T-cell therapy in GBM. We establish that CAR T cells can activate resident myeloid populations and promote endogenous T-cell immunity, emphasizing the importance of host innate and adaptive immunity for CAR T-cell therapy of solid tumors..
嵌合抗原受体 (CAR) T 细胞介导强大的抗原特异性抗肿瘤活性；然而，它们对内源性免疫系统的间接影响尚未得到很好的描述。值得注意的是，我们证明 CAR T 细胞治疗小鼠同源胶质母细胞瘤 (GBM) 会激活肿瘤内髓样细胞，并诱导内源性 T 细胞记忆反应，同时促进 CAR T 细胞反应的前馈传播。CAR T 细胞产生 IFNγ 和宿主免疫细胞对 IFNγ 的反应对于重塑肿瘤免疫景观以促进更活跃和抑制性更小的肿瘤微环境至关重要。这些观察结果的临床相关性得到了研究的支持，这些研究表明，人 IL13Rα2-CAR T 细胞通过 IFNγ 信号激活患者来源的内源性 T 细胞和单核细胞/巨噬细胞，并在一名患有 GBM 的应答患者中诱导产生肿瘤特异性 T 细胞反应。这些研究确立了 CAR T 细胞疗法具有塑造肿瘤微环境的潜力，为引发内源性抗肿瘤免疫创造了允许的环境。意义：我们的发现强调了 IFNγ 信号在 GBM 的 CAR T 细胞治疗中的关键作用。我们证实 CAR T 细胞可以激活固有髓样细胞群并促进内源性 T 细胞免疫，强调宿主先天和适应性免疫对于 CAR T 细胞治疗实体瘤的重要性。
