PO.IM02.04 · 免疫学
将冷肿瘤转化为热肿瘤并克服耐药的免疫策略
The Immune strategies to convert cold to hot tumors and overcome resistances
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作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
冷肿瘤通过限制引流淋巴结内的T细胞启动或限制其向肿瘤微环境（TME）浸润来逃避免疫治疗。在此，我们开发了序贯策略以克服这一局限。首先，我们开发了表达膜结合细胞因子并携带共享或突变抗原的新型mRNA疫苗，以在无毒性的情况下更多、更好地启动肿瘤特异性T细胞（TST）。其次，我们生成了融合入Fc-pro-IL2的四聚体形式NGR，选择性靶向TME中富集的CD13，以提供更多IL-2来重振功能障碍的T细胞。出乎意料的是，在肿瘤血管CD13上顺式递送IL-2可以架起肿瘤血管与TST之间的相互对话。激活的T细胞能够重塑肿瘤血管以允许更多浸润。为维持其抗肿瘤活性，我们序贯递送了由抗PD-1抗体引导的肿瘤激活性细胞因子（pro-IL2）（anti-PD-1-pro-IL2）或放射激活性TLR激动剂，以帮助TME内的DC-T细胞相互作用，从而维持T细胞效应功能。综上，我们建立了将冷肿瘤转化为热肿瘤、进而同时重振TIL的序贯策略，以克服当前免疫疗法的局限。
查看英文原文 English abstract
Cold tumors evade immunotherapy through limiting T cell priming inside draining LN or infiltration into TME. Here, we have developed sequential strategies to overcome the limitation. Firstly, we have developed new mRNA vaccine expressing membrane cytokines with shared or mutated antigens to more and better prime tumor specific T cells (TST) without toxicity. Secondly, we generated tetramer forms of NGR that fusing into Fc-pro-IL2 that selectively targeted CD13 enriched on TME for more IL-2 to rejuvenate dysfunctional T cells. Unexpectedly, cis-delivery of IL-2 on CD13 on tumor vessels can bridge the cross-talk between tumor vessels and TST. Activated T cells can remodel tumor vessels to allow more infiltration. To sustain their anti-tumor activities, we have sequentially delivered tumor-activating cytokines (pro-IL2) guided by anti-PD-1 antibody (anti-PD-1-pro-IL2) or radiation-activating TLR agonists to help DC-T cell interaction inside TME to sustain T-cell effector function. Together, we have sequential strategies converting cold to hot tumors and then simultaneously reinvigorates TIL to overcome the limitations of current immunotherapies.
利益披露 Disclosure
Y. Fu, None.