Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA.
Department of Medical and Molecular Genetics and Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
Nat Commun. 2023 Jan 24;14(1):392. doi: 10.1038/s41467-023-36045-7.
Cancer immunotherapy that deploys the host's immune system to recognize and attack tumors, is a promising strategy for cancer treatment. However, its efficacy is greatly restricted by the immunosuppressive (i.e., immunologically cold) tumor microenvironment (TME). Here, we report an in-situ cryo-immune engineering (ICIE) strategy for turning the TME from immunologically "cold" into "hot". In particular, after the ICIE treatment, the ratio of the CD8 cytotoxic T cells to the immunosuppressive regulatory T cells is increased by more than 100 times in not only the primary tumors with cryosurgery but also distant tumors without freezing. This is achieved by combining cryosurgery that causes "frostbite" of tumor with cold-responsive nanoparticles that not only target tumor but also rapidly release both anticancer drug and PD-L1 silencing siRNA specifically into the cytosol upon cryosurgery. This ICIE treatment leads to potent immunogenic cell death, which promotes maturation of dendritic cells and activation of CD8 cytotoxic T cells as well as memory T cells to kill not only primary but also distant/metastatic breast tumors in female mice (i.e., the abscopal effect). Collectively, ICIE may enable an efficient and durable way to leverage the immune system for combating cancer and its metastasis.
癌症免疫疗法利用宿主的免疫系统识别和攻击肿瘤,是一种有前途的癌症治疗策略。然而,其疗效受到肿瘤微环境(TME)的免疫抑制(即免疫冷)的极大限制。在这里,我们报告了一种原位冷冻免疫工程(ICIE)策略,用于将 TME 从免疫“冷”转变为“热”。具体来说,在 ICIE 治疗后,不仅在接受冷冻手术的原发性肿瘤中,而且在没有冷冻的远处肿瘤中,CD8 细胞毒性 T 细胞与免疫抑制性调节性 T 细胞的比例增加了 100 多倍。这是通过将冷冻手术引起的“冻伤”与冷响应纳米颗粒结合来实现的,这些纳米颗粒不仅靶向肿瘤,而且在冷冻手术后迅速将抗癌药物和 PD-L1 沉默 siRNA 特异性释放到细胞质中。这种 ICIE 治疗导致强烈的免疫原性细胞死亡,促进树突状细胞的成熟和 CD8 细胞毒性 T 细胞以及记忆 T 细胞的激活,不仅可以杀死原发性肿瘤,还可以杀死女性小鼠的远处/转移性乳腺癌(即远隔效应)。总之,ICIE 可能为利用免疫系统对抗癌症及其转移提供一种有效和持久的方法。
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