CTLA-4 immunotherapy exposes differences in immune response along with different tumor progression in colorectal cancer
CTLA-4 immunotherapy exposes differences in immune response along with different tumor progression in colorectal cancer
复制标题
DOI：
10.18632/aging.103765
复制
发表时间：
2020-08-15
期刊：
影响因子：
5.2
通讯作者：
Yang, Yeguo
中科院分区：
文献类型：
--
作者：
Fu, Xiaocong;Luo, Hua;Yang, Yeguo
肿瘤生长伴随着肿瘤微环境的变化和突变，这些突变增加了对治疗的抵抗力。在这里，我们使用同源模型来评估相同类型不同大小的肿瘤的药物反应。我们使用体内功效和Ki-67免疫组织化学（IHC）测定来评估对用相同浓度的抗CTLA-4治疗的应答的差异。流式细胞术分析揭示了免疫亚群的变化在不同的肿瘤生长阶段改变了脾脏、外周血、淋巴结和肿瘤组织。例如，初始CD 4 +T、CD 4 +Tcm、CD 8 +TEM、T、B、Treg、CD 8 +Tcm根据特定的免疫器官表现出不同的百分比。为了进一步揭示免疫微环境的变化，PD-1和CTLA-4的表达水平在不同肿瘤大小的每四种免疫组织的相关亚群中显示出统计学显著差异。此外，在不同动物模型中，相应免疫组织中的CD 4 + Teff/CD 4 + Treg和CD 8 + T/Treg的比率也与肿瘤生长的统计学显著差异相关。这些结果揭示了肿瘤进展过程中免疫微环境的持续变化，抗CTLA-4抗体的免疫治疗效果取决于免疫因子的表达水平。
Tumor growth is accompanied by a changing tumor microenvironment and mutations that increase the resistance to therapy. Here, we used syngeneic models to evaluate the drug response of tumors of the same type of different sizes. We used the in vivo efficacy and Ki-67 immunohistochemistry (IHC) assay to assess the difference in responses in response to treatment with the same concentration of anti-CTLA-4. Flow cytometry analysis revealed changes in the immune subpopulations changes the spleen, peripheral blood, lymph node, and tumor tissue across different tumor growth phases. For example, naive CD4+T, CD4+TCM, CD8+TEM, T, B, Treg, CD8+TCM exhibited different percentages depending on the specific immune organ. To further expose the changes in the immune microenvironment, the level of expression of PD-1 and CTLA-4 showed statistically significant difference in related subsets for each four immune tissues in different tumor sizes. In addition, the ratios of CD4 + Teff/CD4 + Treg and CD8 + T/Treg in corresponding immune tissue were also associated with statistically significant differences alongside tumor growth in different animal models. These results reveal the ongoing changes in the immune microenvironment during tumor progression and anti-CTLA-4 antibody immunotherapy effect depends on the expression level of immune factors.