疫苗增强的 CAR T 细胞与宿主免疫的串扰，以拒绝具有抗原异质性的肿瘤。

Suppr 超能文献

核心技术专利：CN118964589B侵权必究

Suppr 超能文献

核心技术专利：CN118964589B侵权必究

David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.

Cell. 2023 Jul 20;186(15):3148-3165.e20. doi: 10.1016/j.cell.2023.06.002. Epub 2023 Jul 5.

Chimeric antigen receptor (CAR) T cell therapy effectively treats human cancer, but the loss of the antigen recognized by the CAR poses a major obstacle. We found that in vivo vaccine boosting of CAR T cells triggers the engagement of the endogenous immune system to circumvent antigen-negative tumor escape. Vaccine-boosted CAR T promoted dendritic cell (DC) recruitment to tumors, increased tumor antigen uptake by DCs, and elicited the priming of endogenous anti-tumor T cells. This process was accompanied by shifts in CAR T metabolism toward oxidative phosphorylation (OXPHOS) and was critically dependent on CAR-T-derived IFN-γ. Antigen spreading (AS) induced by vaccine-boosted CAR T enabled a proportion of complete responses even when the initial tumor was 50% CAR antigen negative, and heterogeneous tumor control was further enhanced by the genetic amplification of CAR T IFN-γ expression. Thus, CAR-T-cell-derived IFN-γ plays a critical role in promoting AS, and vaccine boosting provides a clinically translatable strategy to drive such responses against solid tumors.

嵌合抗原受体 (CAR) T 细胞疗法有效地治疗人类癌症，但 CAR 识别的抗原丢失构成了主要障碍。我们发现，CAR T 细胞的体内疫苗增强会触发内源性免疫系统的参与，以规避抗原阴性的肿瘤逃逸。疫苗增强的 CAR T 促进树突状细胞 (DC) 向肿瘤募集，增加了 DC 对肿瘤抗原的摄取，并引发了内源性抗肿瘤 T 细胞的激活。这一过程伴随着 CAR T 代谢向氧化磷酸化 (OXPHOS) 的转变，并且严重依赖于 CAR-T 衍生的 IFN-γ。疫苗增强的 CAR T 诱导的抗原扩展 (AS) 使得即使初始肿瘤有 50% 的 CAR 抗原阴性，也能获得部分完全反应，并且通过 CAR T IFN-γ 表达的遗传扩增进一步增强了异质性肿瘤控制。因此，CAR-T 细胞衍生的 IFN-γ 在促进 AS 中发挥关键作用，疫苗增强提供了一种可临床转化的策略，以针对实体瘤驱动这种反应。