State Key Laboratory of Respiratory Disease, Center of Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, 510530, People's Republic of China.
University of Chinese Academy of Sciences, No. 190 Yuquan Road, Beijing, 100049, People's Republic of China.
Cell Commun Signal. 2019 Apr 12;17(1):32. doi: 10.1186/s12964-019-0342-6.
A major challenge in the development of effective cancer immunotherapy is the ability of tumors and their microenvironment to suppress immune cells through immunosuppressive cells such as myeloid -derived suppressor cells and regulatory T cells. We previously demonstrated that Plasmodium infection promotes innate and adaptive immunity against cancer in a murine Lewis lung cancer model but its effects on immunosuppressive cells in the tumor microenvironment are unknown.
Whole Tumors and tumor-derived sorted cells from tumor-bearing mice treated with or without plasmodium infected red blood cells were harvested 17 days post tumor implantation and analyzed using QPCR, western blotting, flow cytometry, and functional assays. Differences between groups were analyzed for statistical significance using Student's t-test.
Here we found that Plasmodium infection significantly reduced the proportions of MDSCs and Tregs in the lung tumor tissues of the treated mice by downregulating their recruiting molecules and blocking cellular activation pathways. Importantly, CD8 T cells isolated from the tumors of Plasmodium-treated mice exhibited significantly higher levels of granzyme B and perforin and remarkably lower levels of PD-1.
We reveal for the first time, the effects of Plasmodium infection on the expansion and activation of MDSCs and Tregs with a consequent elevation of CD8T cell-mediated cytotoxicity within the tumor microenvironment and hold great promise for the development of effective immunotherapeutic strategies.
在开发有效的癌症免疫疗法方面，一个主要挑战是肿瘤及其微环境通过诸如髓源抑制细胞和调节性 T 细胞等免疫抑制细胞来抑制免疫细胞的能力。我们之前证明，疟原虫感染在小鼠 Lewis 肺癌模型中促进了对癌症的先天和适应性免疫，但它对肿瘤微环境中的免疫抑制细胞的影响尚不清楚。
在肿瘤植入后 17 天，从用或不用疟原虫感染的红细胞处理的荷瘤小鼠的整个肿瘤和肿瘤来源的分选细胞中采集肿瘤，并使用 QPCR、western blot、流式细胞术和功能测定进行分析。使用学生 t 检验分析组间差异的统计学意义。
在这里，我们发现疟原虫感染通过下调其募集分子并阻断细胞激活途径，显著降低了治疗小鼠肺部肿瘤组织中 MDSC 和 Treg 的比例。重要的是，从疟原虫处理的小鼠肿瘤中分离出的 CD8 T 细胞表现出显著更高水平的颗粒酶 B 和穿孔素，以及显著更低水平的 PD-1。
我们首次揭示了疟原虫感染对 MDSC 和 Treg 扩增和激活的影响，从而提高了肿瘤微环境中 CD8 T 细胞介导的细胞毒性，为开发有效的免疫治疗策略提供了巨大的希望。
