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Dysfunctional Cd8+ T Cells and the Immune Suppressive Tumor Microenvironment

机译：功能异常的Cd8 + T细胞和免疫抑制肿瘤微环境

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摘要

Although the presence of tumor-infiltrating lymphocytes (TILs) indicates the generation of an endogenous antitumor immune response, immune regulatory pathways can subvert the effector phase and enable tumor escape. Negative regulatory pathways include extrinsic suppression mechanisms but also a T cell-intrinsic dysfunctional state. A more detailed study has been hampered by a lack of cell surface markers defining dysfunctional TILs, and it is clear that PD-1 alone is not sufficient. Our laboratory previously identified the transcription factor Egr2 as a critical component in controlling the anergic state in vitro. Identified Egr2 target genes were used as a means to focus on cell surface markers that might characterize the dysfunctional state, and those with robust staining by flow cytometric analysis were applied towards study of CD8+ T cells in the tumor microenvironment. We found that the Egr2-driven cell surface proteins, LAG-3 and 4-1BB, identify dysfunctional tumor antigen-specific CD8+ TILs. Co-expression of 4-1BB and LAG-3 was seen on a majority of CD8+ T cells within the tumor microenvironment but not in secondary lymphoid organs. Functional analysis revealed defective production of IL-2 and TNF-alpha, while Treg-recruiting chemokines and IFN-gamma remained highly expressed. Transcriptional and flow cytometric characterization identified co-expression of multiple additional co-stimulatory and co-inhibitory receptors by this subset of TIL. Administration of anti-LAG-3 plus anti-4-1BB mAbs was therapeutic against tumors in vivo, which correlated with reversal of TIL dysfunction and restoration of an effector phenotype. The striking feature of heightened and prolonged production of IFN-gamma by T cells within the tumor led us to investigate the role IFN-gamma played during the setting of chronic T cell activation within the tumor site. While IFN-gamma has been reported to be necessary for tumor elimination, IFN-gamma also mediates a form of adaptive resistance by upregulating PD-L1 and indoleamine-2,3-dioxygenase (IDO) in the tumor microenvironment. On the other hand, loss of IFN-gamma sensing by tumor cells has been proposed to lead to secondary resistance to checkpoint blockade therapy. Therefore, to determine whether the effects of IFN-gamma on tumor cells are pro-immune or immune regulatory we rendered tumor cells insensitive to IFN-gamma by selectively mutating the IFNgammaR2 or Jak1 genes in tumor cells. When implanted into mice, IFN-gamma-insensitive tumors were better controlled in vivo. This phenotype was true across several tumor models and was not due to off-target effects from CRISPR/Cas9 mutagenesis. Spontaneous control of mutant tumors was dependent on CD8+ T cells and was associated with a marked increase in the frequency of tumor antigen-specific CD8+ T cells. The mechanism of improved tumor control was mapped to defective PD-L1 upregulation in response to IFN-gamma produced by CD8+ TILs, which phenocopied PD-L1 blockade. Retroviral-mediated re-expression of PD-L1 on IFN-gamma-insensitive tumor cells was sufficient to restore progressive tumor growth. These results indicate that in settings in which the major source of PD-L1 is on tumor cells within the tumor microenvironment, then the dominant effect of IFN-gamma on cancer cells can be immunoregulatory.
机译：尽管肿瘤浸润淋巴细胞（TIL）的存在表明内源性抗肿瘤免疫反应的产生，但免疫调节途径可以破坏效应物相并使肿瘤逃逸。负调控途径包括外在抑制机制，但也包括T细胞内在功能障碍状态。缺乏定义功能障碍性TIL的细胞表面标志物的存在阻碍了更详细的研究，很显然仅靠PD-1是不够的。我们的实验室先前已确定转录因子Egr2是控制体外无氧状态的关键成分。已鉴定的Egr2靶基因被用作关注可能表征功能障碍状态的细胞表面标志物的手段，并且通过流式细胞术分析具有牢固染色的基因被用于研究肿瘤微环境中的CD8 + T细胞。我们发现，Egr2驱动的细胞表面蛋白LAG-3和4-1BB可以识别功能异常的肿瘤抗原特异性CD8 + TIL。在肿瘤微环境中的大多数CD8 + T细胞上可见到4-1BB和LAG-3的共表达，而在次要淋巴器官中则没有。功能分析显示IL-2和TNF-α的产生有缺陷，而Treg募集的趋化因子和IFN-γ仍高表达。转录和流式细胞仪鉴定通过该TIL子集确定了多种其他共刺激和共抑制受体的共表达。抗LAG-3加抗4-1BB mAb的给药对体内肿瘤具有治疗作用，这与TIL功能障碍的逆转和效应子表型的恢复有关。 T细胞在肿瘤内增加和延长IFN-γ产生的显着特征使我们研究了IFN-γ在肿瘤部位慢性T细胞活化过程中的作用。虽然已报道IFN-γ对于消除肿瘤是必需的，但IFN-γ还通过上调肿瘤微环境中的PD-L1和吲哚胺-2,3-二加氧酶（IDO）来介导一种适应性抗性。另一方面，已经提出肿瘤细胞对IFN-γ感测的丧失导致对检查点封锁疗法的继发性抵抗。因此，为了确定IFN-γ对肿瘤细胞的作用是促免疫还是免疫调节，我们通过选择性地突变肿瘤细胞中的IFNgammaR2或Jak1基因，使肿瘤细胞对IFN-γ不敏感。当植入小鼠体内时，对IFN-γ不敏感的肿瘤在体内得到了更好的控制。该表型在几种肿瘤模型中都是正确的，而不是由于CRISPR / Cas9诱变产生的脱靶效应。突变肿瘤的自发控制依赖于CD8 + T细胞，并且与肿瘤抗原特异性CD8 + T细胞频率的显着增加有关。改善的肿瘤控制机制被定位为对CD8 + TILs产生的IFN-γ产生不良的PD-L1上调，表型上PD-L1阻断。逆转录病毒介导的PD-L1在IFN-γ敏感性肿瘤细胞上的重新表达足以恢复肿瘤的生长。这些结果表明，在PD-L1的主要来源在肿瘤微环境内的肿瘤细胞上的情况下，IFN-γ对癌细胞的显性作用可以是免疫调节的。

著录项

  • 作者

    Williams, Jason Bruce.;

  • 作者单位

    The University of Chicago.;

  • 授予单位 The University of Chicago.;
  • 学科 Immunology.
  • 学位 Ph.D.
  • 年度 2018
  • 页码 143 p.
  • 总页数 143
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 宗教;
  • 关键词

  • 入库时间 2022-08-17 11:40:05

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