Optogenetic immunomodulation for adoptive cell transfer therapy

 描述（由申请人提供）：利用肿瘤靶向细胞毒性T淋巴细胞（CTLs）的过继细胞转移（ACT）的基于T细胞的免疫疗法已成为几种类型癌症患者的有力治疗选择。然而，肿瘤经历免疫编辑，导致选择已经建立了有利于其生长的有利微环境或使其能够避免免疫破坏的免疫抑制环境的肿瘤。尽管在临床上取得了有希望的成功，但CTL向肿瘤部位的运输受损、强免疫抑制性肿瘤微环境和脱靶细胞毒性是实现ACT疗法最大益处的主要障碍。 光遗传学是一种结合光学和遗传学技术，通过光学刺激控制遗传修饰的光敏蛋白质来控制特定细胞过程的技术。在这项研究中，我们将使用几种新的光遗传学技术，（1）改善CTL的运输， 肿瘤部位，（2）克服强免疫抑制肿瘤微环境，和（3）防止脱靶细胞毒性。使用光来控制免疫反应避免了与组织直接物理接触的需要，因此避免了对正常功能的任何干扰。重要的是，光提供出色的空间分辨率，允许访问特定的细胞亚型，甚至最小的亚细胞结构域。在临床上，ACT疗法也是各种细胞疗法的常见治疗方式。因此，我们的新型光遗传学方法不仅可用于抗肿瘤免疫疗法，而且可用于不限于白细胞或抗肿瘤环境的潜在疗法。

 DESCRIPTION (provided by applicant): T cell-based immunotherapy utilizing adoptive cell transfer (ACT) of tumor-targeting cytotoxic T lymphocytes (CTLs) has emerged as a powerful treatment option for several types of cancer patients. However, tumors undergo immunoediting, resulting in the selection of tumors that have established either a favorable microenvironment that facilitates their growth or an immunosuppressive environment that enables them to avoid immune destruction. Despite promising successes in the clinic, impaired trafficking of CTLs to tumor sites, strong immunosuppressive tumor microenvironment, and off-target cytotoxicity are main barriers to achieving the maximum benefits of ACT therapy. Optogenetics is a technique that uses a combination of techniques from optics and genetics to control defined cellular processes by controlling genetically modified light-sensitive proteins using optical stimulation. I this study, we will use several novel optogenetic techniques to, (1) improve trafficking of CTLs to tumor sites, (2) overcome strong immunosuppressive tumor microenvironment, and (3) prevent off-target cytotoxicity. The use of light to control immune reactions avoids the need for direct physical contact with the tissue and, therefore, any interference with normal functions. Importantly, light offers outstanding spatial resolution, allowing access to specific cellular subtypes and even the smallest subcellular domains. Clinically, ACT therapy is also a common treatment modality for various cell therapies. Thus, our novel optogenetic approach may have broad applications not only for anti-tumor immunotherapy but also for potential therapies that are not limited to leukocytes or anti-tumor settings.