失眠网,内容丰富有趣,生活中的好帮手!
失眠网 > Cell | 适应性免疫抗性从肿瘤起始干细胞中出现

Cell | 适应性免疫抗性从肿瘤起始干细胞中出现

时间:2024-06-13 04:44:32

相关推荐

Cell | 适应性免疫抗性从肿瘤起始干细胞中出现

Paper Reading

01

Adaptive Immune Resistance Emerges from Tumor- Initiating Stem Cells

Yuxuan Miao, HanseulYang, et al.

Cell,

Tumor-initiating SCs (tSCs) possess a potent capacity for self-renewal and differentiation and, therefore, are often able at low cell numbers to fuel and sustain tumor growth. It has been increasingly recognized that tSCs are endowed with unique molecular features to drive tumorigenesis as well as to promote resistance to cancer therapies. By establishing an effective mouse adoptive cytotoxic T cell transfer (ACT) model in which tSCs can be tracked and directly tested, the authors unearthed compelling evidence that TGF-β-responding tSCs show pronounced resistance to enhanced cytotoxic T cell responses. Furthermore, these TGF-β-responding tSCs are responsible for recurrence following ACT therapy. These SCs express an immune cell ligand, CD80, which when silenced, blunts their resistance to immune surveillance and dampens tumor relapse. In vivo experiments confirmed that a direct interaction between CD80(+) tSCs and CTLA4(+) cytotoxic T cells acts as an important, hitherto unappreciated contributor to resistance to immune surveillance and tumor recurrence in cancer. tSC-derived CD80 also impacted Tregs, whose numbers declined upon tumor-specific Cd80 ablation. As probing deeper into the mechanistic details of tSC CD80 on Treg-mediated suppression of cytotoxic T cells is outside the scope of the current investigation, the authors guessed that it is possible that instead of engaging with CTLA4 on Tregs, tSC CD80 might bind to CD28, which has been reported to be critical for the development of optimal suppressive Treg functions. Interestingly, CD80 was only activated in the subset of tSCs that actively responded to TGF-β, and its expression could be reduced by blocking TGF-βsignaling. Since TGF-β arises in squamous cell carcinomas primarily from the perivasculature and the vasculature of a growing tumor is dynamic, this heterogeneity in the tumor microenvironment implies that the ability of tSCs to resist immunotherapy may change over time. Additionally, the authors also noticed that CD80 expression was not completely abolished upon blocking TGF-β signals, suggesting that additional signaling might function in tSC CD80 activation. How TGF-b signaling might activate CD80 and confer these tumor-evasive mechanisms to SCs is still in its infancy.

/10.1016/j.cell..03.025

02

Functional reprogramming of regulatory T cells in the absence of Foxp3

Louis-MarieCharbonnier, Ye Cui, et al.

Nature Immunology,

Teff cells undergo a profound change in their bioenergetic profile in favor of augmented aerobic glycolysis, oxidative phosphorylation (OXPHOS) and glutaminolysis, as well as the de novo acquisition of biosynthetic pathways such as fatty acid synthesis. Treg cell metabolism is biased towards fatty acid oxidation (FAO) and pyruvate-dependent OXPHOS, whereas glycolysis is kept under strict control. Enforced expression of Foxp3 promotes OXPHOS and suppresses glycolysis. In this paper, the authors demonstrated that the skewing of Treg cells towards a Teff cell–like phenotype on Foxp3 deficiency is critically dependent on a limited set of molecular pathways, including mTORC2 and glycolysis. Furthermore, inhibition of these pathways specifically in Foxp3-deficient Treg cells partially restored regulatory function and attenuated disease. The mechanisms by which mTORC2 dysregulation impairs ∆Treg cell regulatory functions included disruption of Blimp1 and Foxo1- dependent induction of IL-10.Specific deletion of the mTORC2 adaptor gene Rictor in Foxp3-deficient Treg cells ameliorated disease in a Foxo1 transcription factor–dependent manner. Rictordeficiency re-established a subset of Tregcell genetic circuits and suppressed the Teff cell–like glycolytic and respiratory programs, which contributed to immune dysregulation.

/10.1038/s41590-019-0442-x

END

如果觉得《Cell | 适应性免疫抗性从肿瘤起始干细胞中出现》对你有帮助,请点赞、收藏,并留下你的观点哦!

本内容不代表本网观点和政治立场,如有侵犯你的权益请联系我们处理。
网友评论
网友评论仅供其表达个人看法,并不表明网站立场。