Zhang Ying, Gu Aiqin, An Zhijing, Huang Shuai, Zhang Can, Zhong Xiaosong, Hu Yi
Beijing Key Laboratory for Therapeutic Cancer Vaccines, Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China.
The Clinical Center of Gene and Cell Engineering, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China.
Hum Immunol. 2024 Nov;85(6):111093. doi: 10.1016/j.humimm.2024.111093. Epub 2024 Sep 7.
Chimeric antigen receptor (CAR) T cell therapy is a powerful adoptive immunotherapy against blood cancers, but the therapeutic effect was not efficient enough on solid tumors. B cells have been reported to play a critical role in regulating memory T differentiation and cytotoxic T development. However, as of yet the influence of such B cells on CAR T cells has not been discussed. In this study, using ephrin type-A receptor 2 (EphA2) specific CAR T cells, we cultured B cells successfully to stimulate CAR T cells in vitro, and investigated the cell differentiation and anti-tumor efficiency. We observed that EphA2-CAR T cells stimulated by B cells performed increased interferon γ (IFN γ) production and upregulated OX40 expression, as well as the enhanced anti-tumor activity and reduced PD-1 expression. The persistence of CAR T cells was enhanced after B cells stimulation for more than 7 days with the increased subset of central memory T cells (T). In addition, next generation sequencing was performed to explore the underlying mechanisms. The up-regulated genes clustered in, immune response activation, chemokine signaling pathway, calcium signaling pathway, cGMP-PKG signaling pathway and et al. which contributed to the upregulated anti-glioblastoma (GBM) activity of CAR T cells stimulated by B cell. Furthermore, MEF2C, CD40, SYK and TNFRSF13B were upregulated in CAR T cells after co-culturing with B cells. These genes functionally enriched in promoting lymphocytes proliferation and may contribute to the enhanced persistence of CAR T cells. In conclusion, these results indicated the critical role of B cells in prolonging CAR T cells longevity and enhancing anti-tumor activity, which paves the way for the therapeutic exploitation of EphA2-CAR T cells against GBM in the future.
嵌合抗原受体（CAR）T细胞疗法是一种针对血癌的强大过继性免疫疗法，但对实体瘤的治疗效果不够理想。据报道，B细胞在调节记忆T细胞分化和细胞毒性T细胞发育中起关键作用。然而，迄今为止，尚未讨论此类B细胞对CAR T细胞的影响。在本研究中，我们使用 Ephrin A 型受体2（EphA2）特异性CAR T细胞，成功在体外培养B细胞以刺激CAR T细胞，并研究了细胞分化和抗肿瘤效率。我们观察到，B细胞刺激的EphA2-CAR T细胞产生的干扰素γ（IFNγ）增加，OX40表达上调，抗肿瘤活性增强，PD-1表达降低。B细胞刺激超过7天后，CAR T细胞的持久性增强，中枢记忆T细胞（T）亚群增加。此外，进行了下一代测序以探索潜在机制。上调的基因聚集在免疫反应激活、趋化因子信号通路、钙信号通路、cGMP-PKG信号通路等中，这些基因促成了B细胞刺激的CAR T细胞抗胶质母细胞瘤（GBM）活性的上调。此外，与B细胞共培养后，CAR T细胞中的MEF2C、CD40、SYK和TNFRSF13B上调。这些基因在功能上富集于促进淋巴细胞增殖，可能有助于增强CAR T细胞的持久性。总之，这些结果表明B细胞在延长CAR T细胞寿命和增强抗肿瘤活性方面起关键作用，这为未来EphA2-CAR T细胞治疗GBM的开发铺平了道路。
