Sackstein Robert, Schatton Tobias, Barthel Steven R
Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Lab Invest. 2017 Jun;97(6):669-697. doi: 10.1038/labinvest.2017.25. Epub 2017 Mar 27.
Advances in cancer immunotherapy have offered new hope for patients with metastatic disease. This unfolding success story has been exemplified by a growing arsenal of novel immunotherapeutics, including blocking antibodies targeting immune checkpoint pathways, cancer vaccines, and adoptive cell therapy (ACT). Nonetheless, clinical benefit remains highly variable and patient-specific, in part, because all immunotherapeutic regimens vitally hinge on the capacity of endogenous and/or adoptively transferred T-effector (T) cells, including chimeric antigen receptor (CAR) T cells, to home efficiently into tumor target tissue. Thus, defects intrinsic to the multi-step T-cell homing cascade have become an obvious, though significantly underappreciated contributor to immunotherapy resistance. Conspicuous have been low intralesional frequencies of tumor-infiltrating T-lymphocytes (TILs) below clinically beneficial threshold levels, and peripheral rather than deep lesional TIL infiltration. Therefore, a T cell 'homing deficit' may arguably represent a dominant factor responsible for ineffective immunotherapeutic outcomes, as tumors resistant to immune-targeted killing thrive in such permissive, immune-vacuous microenvironments. Fortunately, emerging data is shedding light into the diverse mechanisms of immune escape by which tumors restrict T cell trafficking and lesional penetrance. In this review, we scrutinize evolving knowledge on the molecular determinants of T cell navigation into tumors. By integrating recently described, though sporadic information of pivotal adhesive and chemokine homing signatures within the tumor microenvironment with better established paradigms of T-cell trafficking under homeostatic or infectious disease scenarios, we seek to refine currently incomplete models of T cell entry into tumor tissue. We further summarize how cancers thwart homing to escape immune-mediated destruction and raise awareness of the potential impact of immune checkpoint blockers on T cell homing. Finally, we speculate on innovative therapeutic opportunities for augmenting T cell homing capabilities to improve immunotherapy-based tumor eradication in cancer patients, with special focus on malignant melanoma.
癌症免疫疗法的进展为转移性疾病患者带来了新希望。这一不断展现的成功故事体现在越来越多的新型免疫疗法上，包括针对免疫检查点通路的阻断抗体、癌症疫苗和过继性细胞疗法（ACT）。然而，临床益处仍然高度可变且因人而异，部分原因是所有免疫治疗方案都至关重要地依赖于内源性和/或过继性转移的T效应（T）细胞，包括嵌合抗原受体（CAR）T细胞，有效归巢到肿瘤靶组织的能力。因此，多步骤T细胞归巢级联中固有的缺陷已成为免疫治疗耐药性的一个明显但未得到充分认识的因素。明显的是，肿瘤浸润性T淋巴细胞（TILs）在瘤内的频率低于临床有益阈值水平，且TIL浸润集中在周边而非深部病灶。因此，T细胞“归巢缺陷”可以说是导致免疫治疗效果不佳的主要因素，因为对免疫靶向杀伤有抗性的肿瘤在这种允许的、免疫空虚的微环境中茁壮成长。幸运的是，新出现的数据正在揭示肿瘤限制T细胞 trafficking 和病灶穿透的多种免疫逃逸机制。在本综述中，我们仔细研究了关于T细胞导航到肿瘤的分子决定因素的不断发展的知识。通过将肿瘤微环境中关键的黏附分子和趋化因子归巢特征的最新描述（尽管是零星信息）与稳态或感染性疾病情况下更好确立的T细胞 trafficking 范式相结合，我们试图完善目前不完整的T细胞进入肿瘤组织的模型。我们进一步总结了癌症如何阻碍归巢以逃避免疫介导的破坏，并提高对免疫检查点阻滞剂对T细胞归巢潜在影响的认识。最后，我们推测了增强T细胞归巢能力以改善癌症患者基于免疫疗法的肿瘤根除的创新治疗机会，特别关注恶性黑色素瘤。
