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美国麻省理工学院Darrell J. Irvine等研究人员合作发现，疫苗促进的CAR T与宿主免疫交流来拒绝具有抗原异质性的肿瘤。2023年7月5日，国际知名学术期刊《细胞》在线发表了这一成果。

研究人员发现，嵌合抗原受体（CAR）T细胞的体内疫苗加强引发了内源性免疫系统的参与，从而规避抗原阴性的肿瘤逃逸。疫苗增强的CAR T促进了树突状细胞（DC）对肿瘤的招募，增加了DC对肿瘤抗原的摄取，并激发了内源性抗肿瘤T细胞的启动。这一过程伴随着CAR T代谢向氧化磷酸化（OXPHOS）的转变，并且关键依赖于CAR T衍生的IFN-γ。

由疫苗增强的CAR T诱导的抗原扩散（AS）使一部分完全反应成为可能，即使最初的肿瘤有50%的CAR抗原是阴性的，而异质性的肿瘤控制通过CAR T IFN-γ表达的基因扩增得到进一步加强。因此，CAR-T细胞衍生的IFN-γ在促进AS方面起着关键作用，而疫苗增强提供了一种临床上可转化的策略，以推动对实体瘤的这种反应。

据悉，CAR T细胞疗法能有效地治疗人类癌症，但CAR识别的抗原的丧失构成了一个主要障碍。

附：英文原文

Title: Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity

Author: Leyuan Ma, Alexander Hostetler, Duncan M. Morgan, Laura Maiorino, Ina Sulkaj, Charles A. Whittaker, Alexandra Neeser, Ivan Susin Pires, Parisa Yousefpour, Justin Gregory, Kashif Qureshi, Jonathan Dye, Wuhbet Abraham, Heikyung Suh, Na Li, J. Christopher Love, Darrell J. Irvine

Issue&Volume: 2023-07-05

Abstract: 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.

DOI: 10.1016/j.cell.2023.06.002

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00642-6