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\ Paper Reading 01 NF-κB c-Rel Is Crucial for the Regulatory T Cell Immune Checkpoint in Cancer Yenkel Grinberg-Bleyer, Hyunju Oh, Alexis Desrichard, Dev M. Bhatt, et al. Cell, 2017 Regulatory T cells (Tregs) play a pivotal role in the inhibition of anti-tumor immune responses. Understanding the mechanisms governing Treg homeostasis may be important for the development of effective tumor immunotherapy. In this report, the authors showed that NF-κB c-Rel ablation specifically impairs the generation and maintenance of the activated Treg (aTreg) subset, which is known to be enriched at sites of tumors. Using mouse models, they demonstrate that melanoma growth is drastically reduced in mice lacking c-Rel, but not p65, in Tregs. Moreover, chemical inhibition of c-Rel function delayed melanoma growth by impairing aTreg-mediated immunosuppression and potentiated the effects of anti-PD-1 immunotherapy. In summary, NF-κB c-Rel is critical for the function of activated Tregs and serves as a target to reduce Treg function in the tumor microenvironment without compromising systemic tolerance or causing autoimmunity. This paper is not clear about how c-Rel affects the molecular mechanism of Treg differentiation. However, the effect of c-Rel inhibitor and anti-PD-1 combined treatment on xenografting melanoma mice is quite exciting. This is certainly a hope for patients with poor clinical efficacy of tumor immunotherapy, and a successful model and breakthrough in translational medicine research (although the results of the final clinical trials are unknown). https:///10.1016/j.cell.2017.08.004 02 Shao-Lai Zhou, Zheng-Jun Zhou, Zhi-Qiang Hu, Xiao-Wu Huang, et al. Gastroenterology, 2016Neutrophils can either promote or inhibit tumor progression, depending on the tumor microenvironment, via release of cytokines. Neither the factors produced by tumor-associated neutrophils (TANs) nor their effects on tumor progression have been characterized. We investigated the roles of TANs in progression of hepatocellular carcinoma (HCC) using cell lines and immune cells isolated from patients. Firstly, the authors found that HCC TANs express high levels of CCL2 and CCL17. TANs recruit macrophages and Treg cells to facilitate HCC neovascularization and progression through CCL2 and CCL17. HCC cells educated nPBNs to gain TAN-like characteristics through PI3K/Akt and p38/MAPK signaling. Sorafenib treatment increased the intratumoral infiltration of neutrophils. Depletion of TANs inhibited tumor growth and angiogenesis when combined with sorafenib. Lastly, they demonstrated TAN counts were correlated with the number of intratumoral macrophages and Treg cells, MVD, prognosis, and the response to sorafenib in HCC patients. In this study, the authors unveiled that relationship and interactions between TANs and HCCs, which is significant mechanism of tumor microenvironment. http://dx./10.1053/j.gastro.2016.02.040 END |
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