Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
Nat Biomed Eng. 2022 Feb;6(2):129-143. doi: 10.1038/s41551-021-00831-9. Epub 2022 Jan 10.
Anti-tumour inflammatory cytokines are highly toxic when administered systemically. Here, in multiple syngeneic mouse models, we show that the intratumoural injection of recombinantly expressed cytokines bound tightly to the common vaccine adjuvant aluminium hydroxide (alum) (via ligand exchange between hydroxyls on the surface of alum and phosphoserine residues tagged to the cytokine by an alum-binding peptide) leads to weeks-long retention of the cytokines in the tumours, with minimal side effects. Specifically, a single dose of alum-tethered interleukin-12 induced substantial interferon-γ-mediated T-cell and natural-killer-cell activities in murine melanoma tumours, increased tumour antigen accumulation in draining lymph nodes and elicited robust tumour-specific T-cell priming. Moreover, intratumoural injection of alum-anchored cytokines enhanced responses to checkpoint blockade, promoting cures in distinct poorly immunogenic syngeneic tumour models and eliciting control over metastases and distant untreated lesions. Intratumoural treatment with alum-anchored cytokines represents a safer and tumour-agnostic strategy to improving local and systemic anticancer immunity.
抗肿瘤炎症细胞因子全身给药时毒性很高。在这里，我们在多个同基因小鼠模型中表明，将重组表达的细胞因子通过与铝佐剂（ alum ）表面的羟基之间的配体交换（通过与细胞因子上的磷酸丝氨酸残基连接的 alum 结合肽标记）紧密结合到肿瘤内注射，可导致细胞因子在肿瘤中保留数周，副作用最小。具体来说，单次剂量的 alum 结合的白细胞介素-12 在小鼠黑色素瘤肿瘤中诱导了大量的干扰素-γ介导的 T 细胞和自然杀伤细胞活性，增加了引流淋巴结中的肿瘤抗原积累，并引发了强烈的肿瘤特异性 T 细胞启动。此外，肿瘤内注射 alum 锚定的细胞因子增强了对检查点阻断的反应，在不同的免疫原性差的同基因肿瘤模型中促进了治愈，并控制了转移和未治疗的远处病变。用 alum 锚定的细胞因子进行肿瘤内治疗代表了一种更安全且与肿瘤无关的策略，可改善局部和全身抗癌免疫。
