全身施用细胞因子是有效的免疫治疗剂，但可能导致严重的剂量限制性毒性。为了克服这一挑战，细胞因子被设计用于局部分娩后瘤内保留。然而，尽管诱导治疗的病变消退，但肿瘤局部细胞因子通常仅在远端未治疗的肿瘤中引起适度的反应。在本研究中，我们报告了一种局部细胞因子疗法，通过靶向普遍存在的白细胞受体 CD45，安全地引发全身抗肿瘤免疫。相对于野生型对应物，CD45 靶向免疫细胞因子具有较低的内化率，导致淋巴细胞之间持续的下游顺式和反式信号传导。在多个同基因小鼠肿瘤模型中，单剂量瘤内注射αCD45-白细胞介素（IL）-12，随后注射单剂量αCD45-IL-15，可根除已治疗的肿瘤和未治疗的远端病变，且无毒性。从机制上讲，靶向 CD45 的细胞因子对肿瘤引流淋巴结中的肿瘤特异性 CD8 T 细胞进行了重新编程，使其具有抗病毒转录特征。 CD45 锚定代表了宿主免疫细胞保留蛋白质用于免疫治疗的广泛平台。© 2024。作者。

Systemically administered cytokines are potent immunotherapeutics but can cause severe dose-limiting toxicities. To overcome this challenge, cytokines have been engineered for intratumoral retention after local delivery. However, despite inducing regression of treated lesions, tumor-localized cytokines often elicit only modest responses at distal untreated tumors. In the present study, we report a localized cytokine therapy that safely elicits systemic antitumor immunity by targeting the ubiquitous leukocyte receptor CD45. CD45-targeted immunocytokines have lower internalization rates relative to wild-type counterparts, leading to sustained downstream cis and trans signaling between lymphocytes. A single intratumoral dose of αCD45-interleukin (IL)-12 followed by a single dose of αCD45-IL-15 eradicated treated tumors and untreated distal lesions in multiple syngeneic mouse tumor models without toxicity. Mechanistically, CD45-targeted cytokines reprogrammed tumor-specific CD8+ T cells in the tumor-draining lymph nodes to have an antiviral transcriptional signature. CD45 anchoring represents a broad platform for protein retention by host immune cells for use in immunotherapy.© 2024. The Author(s).