美国麻省理工学院Darrell J. Irvine等研究人员合作发现，局部递送细胞表面靶向免疫细胞因子可编程系统性抗肿瘤免疫。相关论文于2024年8月7日在线发表在《自然—免疫学》杂志上。

研究人员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安全地引发系统性抗肿瘤免疫。CD45靶向的免疫细胞因子相比于野生型对照具有较低的内化率，从而导致淋巴细胞之间持续的顺向和逆向信号传导。

单次肿瘤内注射αCD45-白介素（IL）-12，随后单次注射αCD45-IL-15，在多个同源小鼠肿瘤模型中消除了处理过的肿瘤和未处理的远处病变且无毒性。

机制上，CD45靶向的细胞因子重新编程了肿瘤引流淋巴结中的肿瘤特异性CD8⁺ T细胞，使其具有抗病毒的转录特征。CD45固定代表了一种广泛的平台，通过宿主免疫细胞用于免疫治疗。

研究人员表示，系统性给药的细胞因子是强效的免疫治疗药物，但可能会引起严重的剂量限制毒性。为克服这一挑战，细胞因子已被设计用于局部递送后在肿瘤内保留。然而，尽管能引起治疗部位的肿瘤退化，肿瘤局部化的细胞因子通常在远处未处理的肿瘤中仅引起轻微的反应。

附：英文原文

Title: Local delivery of cell surface-targeted immunocytokines programs systemic antitumor immunity

Author: Santollani, Luciano, Maiorino, Laura, Zhang, Yiming J., Palmeri, Joseph R., Stinson, Jordan A., Duhamel, Lauren R., Qureshi, Kashif, Suggs, Jack R., Porth, Owen T., Pinney, William, Msari, Riyam Al, Walsh, Agnes A., Wittrup, K. Dane, Irvine, Darrell J.

Issue&Volume: 2024-08-07

Abstract: 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.

DOI: 10.1038/s41590-024-01925-7

Source: https://www.nature.com/articles/s41590-024-01925-7