Cell Reprogramming in Hematopoiesis and Immunity Laboratory, Lund Stem Cell Center, Department of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden.
Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden.
Front Immunol. 2021 Jul 21;12:714822. doi: 10.3389/fimmu.2021.714822. eCollection 2021.
Advances in understanding how cancer cells interact with the immune system allowed the development of immunotherapeutic strategies, harnessing patients' immune system to fight cancer. Dendritic cell-based vaccines are being explored to reactivate anti-tumor adaptive immunity. Immune checkpoint inhibitors and chimeric antigen receptor T-cells (CAR T) were however the main approaches that catapulted the therapeutic success of immunotherapy. Despite their success across a broad range of human cancers, many challenges remain for basic understanding and clinical progress as only a minority of patients benefit from immunotherapy. In addition, cellular immunotherapies face important limitations imposed by the availability and quality of immune cells isolated from donors. Cell fate reprogramming is offering interesting alternatives to meet these challenges. Induced pluripotent stem cell (iPSC) technology not only enables studying immune cell specification but also serves as a platform for the differentiation of a myriad of clinically useful immune cells including T-cells, NK cells, or monocytes at scale. Moreover, the utilization of iPSCs allows introduction of genetic modifications and generation of T/NK cells with enhanced anti-tumor properties. Immune cells, such as macrophages and dendritic cells, can also be generated by direct cellular reprogramming employing lineage-specific master regulators bypassing the pluripotent stage. Thus, the cellular reprogramming toolbox is now providing the means to address the potential of patient-tailored immune cell types for cancer immunotherapy. In parallel, development of viral vectors for gene delivery has opened the door for reprogramming in regenerative medicine, an elegant strategy circumventing the current limitations of cell manipulation. An analogous paradigm has been recently developed in cancer immunotherapy by the generation of CAR T-cells . These new ideas on endogenous reprogramming, cross-fertilized from the fields of regenerative medicine and gene therapy, are opening exciting avenues for direct modulation of immune or tumor cells , widening our strategies to remove cancer immunotherapy roadblocks. Here, we review current strategies for cancer immunotherapy, summarize technologies for generation of immune cells by cell fate reprogramming as well as highlight the future potential of inducing these unique cell identities , providing new and exciting tools for the fast-paced field of cancer immunotherapy.
对癌细胞如何与免疫系统相互作用的认识的进步使得免疫治疗策略得以发展，利用患者的免疫系统来对抗癌症。树突状细胞疫苗正在被探索以重新激活抗肿瘤适应性免疫。然而，免疫检查点抑制剂和嵌合抗原受体 T 细胞（CAR T）是推动免疫疗法治疗成功的主要方法。尽管它们在广泛的人类癌症中取得了成功，但对于基础理解和临床进展仍存在许多挑战，因为只有少数患者受益于免疫疗法。此外，细胞免疫疗法面临着从供体中分离免疫细胞的可用性和质量所带来的重要限制。细胞命运重编程为应对这些挑战提供了有趣的替代方案。诱导多能干细胞（iPSC）技术不仅使研究免疫细胞的特化成为可能，而且还为分化出大量临床上有用的免疫细胞提供了一个平台，包括 T 细胞、NK 细胞或单核细胞。此外，利用 iPSC 可以引入遗传修饰，并产生具有增强的抗肿瘤特性的 T/NK 细胞。免疫细胞，如巨噬细胞和树突状细胞，也可以通过直接使用谱系特异性主调控因子进行细胞重编程来产生，绕过多能阶段。因此，细胞重编程工具包现在提供了一种方法，可以针对癌症免疫疗法的患者定制免疫细胞类型的潜力。与此同时，用于基因传递的病毒载体的发展为再生医学中的重编程打开了大门，这是一种规避当前细胞操作限制的优雅策略。最近，在癌症免疫疗法中，通过生成 CAR T 细胞，也开发了类似的范例。这些来自再生医学和基因治疗领域的内源性重编程的新想法，为直接调节免疫或肿瘤细胞开辟了令人兴奋的途径，拓宽了我们消除癌症免疫疗法障碍的策略。在这里，我们回顾了癌症免疫疗法的当前策略，总结了通过细胞命运重编程生成免疫细胞的技术，并强调了诱导这些独特细胞身份的未来潜力，为快速发展的癌症免疫治疗领域提供了新的令人兴奋的工具。
