SCI
2 September 2024
Local delivery of cell surface-targeted immunocytokines programs systemic antitumor immunity
(Nature immunology;IF:27.7)
Santollani L, Maiorino L, Zhang YJ, Palmeri JR, Stinson JA, Duhamel LR, Qureshi K, Suggs JR, Porth OT, Pinney W 3rd, Msari RA, Walsh AA, Wittrup KD, Irvine DJ. Local delivery of cell surface-targeted immunocytokines programs systemic antitumor immunity. Nat Immunol. 2024 Aug 7. doi: 10.1038/s41590-024-01925-7. Epub ahead of print. PMID: 39112631.
Corresponding author:
K. Dane Wittrup, Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
e-mail: wittrup@mit.edu
Darrell J. Irvine, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
e-mail: djirvine@mit.edu
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.
全身给药的细胞因子是强效的免疫治疗药物,但可能引起严重的剂量限制性毒性。为了克服这一挑战,细胞因子已被设计用于局部递送后在肿瘤内滞留。然而,尽管可以诱导治疗病灶的消退,但肿瘤局部的细胞因子对远处未治疗的肿瘤通常仅产生适度的反应。在本研究中,我们报告了一种局部细胞因子疗法,该疗法通过靶向广泛存在的白细胞受体CD45,安全地引发全身抗肿瘤免疫反应。与野生型同类药物相比,CD45靶向免疫细胞因子的内化率低于野生型,从而导致淋巴细胞之间持续的顺式和反式信号传导。在多个同基因小鼠肿瘤模型中,单次瘤内注射的αCD45-白介素(IL)-12然后再单次注射αCD45-IL-15,可消除已治疗的肿瘤和未治疗的远处病灶,且无毒性。从机制上讲,靶向CD45的细胞因子重编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锚定代表了一种宿主免疫细胞保留用于免疫治疗的蛋白质的广泛平台。