Adaptive Immunity Laboratory, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano (Milano), Italy.
Adaptive Immunity Laboratory, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano (Milano), Italy; Humanitas University, Via Manzoni 113, Rozzano (Milano), Italy.
Cytokine Growth Factor Rev. 2017 Aug;36:107-116. doi: 10.1016/j.cytogfr.2017.06.009. Epub 2017 Jun 23.
Cytotoxic T lymphocytes (cytotoxic T cells, CTLs) are an immune effector cell population that can mediate specific immune responses against cancer. Based on this concept, tumor immunotherapy protocols have been developed using adoptive transfer of in vitro-expanded autologous T cells that can kill cancer cells. However, fully functional adoptive T cell therapies (ACT) are hampered by the inability to guarantee that all transferred T cells manage to reach the tumor sites and make contact with cancer cells. The lack of tumor homing of T cells may be caused by a variety of reasons. Stromal architecture and biological features of the tumor microenvironment may act as barriers to T cell migration. A mismatch between the chemokines released by the tumor or tumor stroma and the chemokine receptors expressed on the transferred T cells may also impede T cell homing. The identification of mechanisms responsible for cancer stroma remodeling is helping to overcome the barriers of access to tumors, via novel therapeutic strategies targeting tumor-stroma interactions. Simultaneously, recent studies have demonstrated ways through which virally-transduced CTLs can be made to express suitable chemokine receptors so as to enhance ACT, by improving CTL homing into the tumor. Here we review the most important findings related to T cell trafficking to the tumor, highlighting contributions that have led to promising improvements in the available T cell therapy strategies. We discuss new possible combinatorial strategies aimed to overcome chemokine mismatch, physical and biological barriers and immunosuppression, so as to achieve more effective ACT therapies.
细胞毒性 T 淋巴细胞（cytotoxic T cells，CTLs）是一种免疫效应细胞群体，能够介导针对癌症的特异性免疫反应。基于这一概念，已经开发了使用体外扩增的自体 T 细胞过继转移的肿瘤免疫治疗方案，这些 T 细胞能够杀死癌细胞。然而，完全功能性的过继性 T 细胞治疗（adoptive T cell therapy，ACT）受到了阻碍，因为无法保证所有转移的 T 细胞都能够到达肿瘤部位并与癌细胞接触。T 细胞缺乏向肿瘤归巢可能是由多种原因引起的。肿瘤微环境中的基质结构和生物学特征可能会阻碍 T 细胞的迁移。肿瘤或肿瘤基质释放的趋化因子与转移 T 细胞上表达的趋化因子受体之间的不匹配也可能阻碍 T 细胞归巢。识别导致癌症基质重塑的机制有助于通过针对肿瘤-基质相互作用的新型治疗策略来克服进入肿瘤的障碍。同时，最近的研究表明，通过使病毒转导的 CTLs 表达合适的趋化因子受体，可以改善 CTL 向肿瘤的归巢，从而增强 ACT。在这里，我们综述了与 T 细胞向肿瘤转移相关的最重要发现，强调了这些发现为改进现有的 T 细胞治疗策略做出的贡献。我们讨论了新的可能的组合策略，旨在克服趋化因子不匹配、物理和生物学障碍以及免疫抑制，以实现更有效的 ACT 治疗。
