Synergy between CD8 T Cells and Th1 or Th2 Polarised CD4 T Cells for Adoptive Immunotherapy of Brain Tumours

The feasibility of cancer immunotherapy mediated by T lymphocytes is now a clinical reality. Indeed, many tumour associated antigens have been identified for cytotoxic CD8 T cells, which are believed to be key mediators of tumour rejection. However, for aggressive malignancies in specialised anatomic sites such as the brain, a limiting factor is suboptimal tumour infiltration by CD8 T cells. Here we take advantage of recent advances in T cell biology to differentially polarise CD4 T cells in order to explore their capacity to enhance immunotherapy. We used an adoptive cell therapy approach to work with clonal T cell populations of defined specificity. Th1 CD4 T cells preferentially homed to and accumulated within intracranial tumours compared with Th2 CD4 T cells. Moreover, tumour-antigen specific Th1 CD4 T cells enhanced CD8 T cell recruitment and function within the brain tumour bed. Survival of mice bearing intracranial tumours was significantly prolonged when CD4 and CD8 T cells were co-transferred. These results should encourage further definition of tumour antigens recognised by CD4 T cells, and exploitation of both CD4 and CD8 T cell subsets to optimise T cell therapy of cancer.

由T淋巴细胞介导的癌症免疫治疗（cancer immunotherapy）现已成为临床现实。目前已鉴定出多种可被细胞毒性CD8 T细胞（cytotoxic CD8 T cells）识别的肿瘤相关抗原，此类细胞被认为是介导肿瘤排斥反应的关键效应群体。然而，针对脑等特殊解剖部位的侵袭性恶性肿瘤，CD8 T细胞（CD8 T cells）对肿瘤组织的浸润不足是制约治疗效果的关键因素之一。
本研究依托T细胞生物学领域的最新研究进展，通过对CD4 T细胞（CD4 T cells）进行差异化极化，旨在探索其增强癌症免疫治疗效果的潜力。我们采用过继细胞治疗（adoptive cell therapy）策略，使用具有明确抗原特异性的克隆性T细胞群体开展实验。结果显示，相较于Th2型CD4 T细胞，Th1型CD4 T细胞更倾向于归巢并聚集于颅内肿瘤组织中。此外，肿瘤抗原特异性的Th1型CD4 T细胞可促进CD8 T细胞在脑肿瘤床内的招募与功能活化。当联合输注CD4与CD8 T细胞时，携带颅内肿瘤的小鼠生存期得到显著延长。
上述研究结果将推动对CD4 T细胞识别的肿瘤抗原的进一步界定，并为同时利用CD4与CD8 T细胞亚群优化肿瘤T细胞治疗提供重要的理论支撑。