Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Cancer Immunol Immunother. 2020 Jul;69(7):1279-1292. doi: 10.1007/s00262-020-02540-9. Epub 2020 Mar 17.
The presence of activated T cells in colorectal cancer tissues is a strong predictor of patient survival. Our previous studies have shown that regulatory T cells (Treg) are able to reduce T cell transendothelial migration in vitro and accumulation of effector T cells in intestinal tumors in vivo in the murine APC model for microsatellite stable intestinal tumors. In this study, we investigated the effect of Treg depletion on the density and effector functions of different TCRαβ and TCRγδ T cell populations in intestinal tumors. We used the APC\DEREG mouse model, which harbor a diphtheria toxin receptor under the control of the FOXP3 promoter, to deplete Treg in tumor bearing mice. We found that the density of conventional TCRαβCD8αβ T cells was significantly increased in Treg-depleted tumors in comparison with Treg-proficient tumors. Furthermore, TCRαβCD8αβ T cells showed increased proliferation and activation as well as increased Granzyme B and IFN-γ production in Treg-depleted tumors. In sharp contrast, the densities and effector functions of TCRαβCD8αα T cells and TCRγδ T cells remained unchanged by Treg depletion. We also documented a distinct population of IL-17ATNF TCRγδCD8 T cells in tumors, which were not affected by Treg depletion. We conclude that Treg depletion affects only conventional TCRαβCD8αβ T cells in intestinal tumors, while unconventional T cells and T cells in unaffected tissue are not altered. Immunotherapies aimed at depleting Treg from tumors may thus be a viable option for reinvigoration of conventional cytotoxic T cells with a Th1 cytokine profile.
在结直肠癌细胞组织中存在活化的 T 细胞是患者生存的有力预测指标。我们之前的研究表明，调节性 T 细胞（Treg）能够减少体外 T 细胞跨内皮迁移和体内小鼠 APC 模型中微卫星稳定肠肿瘤中效应 T 细胞在肠道肿瘤中的积累。在这项研究中，我们研究了 Treg 耗竭对肠道肿瘤中不同 TCRαβ 和 TCRγδ T 细胞群的密度和效应功能的影响。我们使用了 APC\DEREG 小鼠模型，该模型在 FOXP3 启动子的控制下携带白喉毒素受体，以在荷瘤小鼠中耗竭 Treg。我们发现，与 Treg 丰富的肿瘤相比，Treg 耗竭的肿瘤中常规 TCRαβCD8αβ T 细胞的密度显着增加。此外，TCRαβCD8αβ T 细胞在 Treg 耗竭的肿瘤中表现出增加的增殖和激活以及增加的颗粒酶 B 和 IFN-γ 产生。相比之下，Treg 耗竭对 TCRαβCD8αα T 细胞和 TCRγδ T 细胞的密度和效应功能没有影响。我们还记录了肿瘤中存在独特的 IL-17ATNF TCRγδCD8 T 细胞群，Treg 耗竭对其没有影响。我们得出结论，Treg 耗竭仅影响肠道肿瘤中的常规 TCRαβCD8αβ T 细胞，而未受影响的组织中的非常规 T 细胞和 T 细胞没有改变。因此，从肿瘤中耗竭 Treg 的免疫疗法可能是重振具有 Th1 细胞因子特征的常规细胞毒性 T 细胞的可行选择。
