Amrita School of Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi 682041, Kerala, India.
Department of Medical Oncology and Hematology, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Kochi 682041, Kerala, India.
Int Immunopharmacol. 2023 Jul;120:110129. doi: 10.1016/j.intimp.2023.110129. Epub 2023 May 16.
Tumor microenvironment (TME) is a heterogeneous system consisting of both cellular and acellular components. The growth and progression of tumors rely greatly on the nature of TME, marking it as an important target in cancer immunotherapy. Lewis Lung Carcinoma (LLC) is an established murine lung cancer model representing immunologically 'cold' tumors characterized by very few infiltrated cytotoxic T-cells, high levels of Myeloid-Derived Suppressor Cells (MDSCs) and Tumor-Associated Macrophages (TAMs). Here, we report various strategies we applied to reverse the non-immunogenic character of this cold tumor by imparting: a) immunogenic cell death using Hypericin nanoparticle-based photodynamic therapy (PDT), b) repolarising TAM using a TLR7/8 agonist, resiquimod, c) immune checkpoint inhibition using anti-PD-L1 and d) depleting MDSCs using low-dose 5-fluorouracil (5-FU) chemotherapy. Interestingly, the nano-PDT, resiquimod or anti-PD-L1 treatment had no major impact on tumor growth, whereas low-dose 5-FU-mediated depletion of MDSCs showed significant anti-tumor effect, primarily caused by the increased infiltration of CD8 cytotoxic T-cells (∼96%). Though we have tested combining PDT with resiquimod or 5-FU for any synergistic effect, low-dose 5-FU alone showed better response than combinations. In effect, we show that depletion of MDSCs using low-dose 5-FU was one of the best methods to augment infiltration of CD8 cytotoxic T-cells into a cold tumor, which is resistant to conventional therapies including immune checkpoint inhibitors.
肿瘤微环境（TME）是一个由细胞和无细胞成分组成的异质系统。肿瘤的生长和进展在很大程度上依赖于 TME 的性质，这使其成为癌症免疫治疗的重要靶点。Lewis 肺癌（LLC）是一种已建立的小鼠肺癌模型，代表免疫“冷”肿瘤，其特征是浸润的细胞毒性 T 细胞很少，髓源抑制细胞（MDSCs）和肿瘤相关巨噬细胞（TAMs）水平很高。在这里，我们报告了我们应用各种策略来逆转这种冷肿瘤的非免疫原性特征，这些策略包括：a）使用血啉纳米颗粒基光动力疗法（PDT）诱导免疫原性细胞死亡，b）使用 TLR7/8 激动剂瑞喹莫德重新极化 TAM，c）使用抗 PD-L1 进行免疫检查点抑制，d）使用低剂量 5-氟尿嘧啶（5-FU）化疗耗尽 MDSCs。有趣的是，纳米 PDT、瑞喹莫德或抗 PD-L1 治疗对肿瘤生长没有重大影响，而低剂量 5-FU 介导的 MDSCs 耗竭显示出显著的抗肿瘤作用，主要是由于 CD8 细胞毒性 T 细胞的浸润增加（约 96%）。尽管我们已经测试了将 PDT 与瑞喹莫德或 5-FU 联合使用以获得任何协同效应，但低剂量 5-FU 单独使用的反应要好于联合使用。实际上，我们表明，使用低剂量 5-FU 耗尽 MDSCs 是增强 CD8 细胞毒性 T 细胞浸润冷肿瘤的最佳方法之一，而冷肿瘤对包括免疫检查点抑制剂在内的常规疗法具有抗性。
