1、腫瘤微環(huán)境內(nèi)對免疫檢查點抑制劑的抗性機制目錄第一章 背景第一節(jié) 免疫檢查點第二節(jié) 腫瘤的策略第三節(jié) 治療的對策第四節(jié) 面臨的挑戰(zhàn)第二章 腫瘤微環(huán)境內(nèi)對免疫檢查點抑制劑的抗性機制第一節(jié) 腫瘤微環(huán)境內(nèi)的免疫調(diào)節(jié)通路第二節(jié) 表觀遺傳沉默趨化因子分泌第三節(jié) I型干擾素信號第三章 展望組合治療的發(fā)展前景第一節(jié) 從小鼠模型到臨床研究第二節(jié) 減少免疫調(diào)節(jié)細胞第三節(jié) 適用范圍第四節(jié) 其它的思考 參考文獻第一章：背景第一節(jié) 免疫檢查點免疫檢查點(immune checkpoint)：免疫系統(tǒng)中的一些“抑制性信號”或“抑制性分子”，限制免疫應(yīng)答的持續(xù)時間和范圍。Pardoll DM. Nat Rev Cancer

2、. 2012 Mar 22;12(4):252-64CTLA-4 與 PD-1/PD-L1Pardoll DM. Nat Rev Cancer. 2012 Mar 22;12(4):252-64第二節(jié) 腫瘤的策略Pardoll DM. Nat Rev Cancer. 2012 Mar 22;12(4):252-64第三節(jié) 治療的對策Sharma P and Allison JP. Science. 2015 Apr 3;348(6230):56-6Buqu, A., et al. OncoImmunology, 2015. 4(4): p. e1008814.免疫檢查點抑制劑 (Immune

3、Checkpoint Blockades，ICBs)Robert C et al. N Engl J Med 2011;364:2517-2526.第四節(jié) 面臨的挑戰(zhàn)第二章：腫瘤微環(huán)境內(nèi)對免疫檢查點抑制劑的抗性機制腫瘤微環(huán)境Fridman W H, Pags F, Sauts-Fridman C, et al. Nature Reviews Cancer, 2012, 12(4): 298-306.Lee, L., M. Gupta and S. Sahasranaman. The Journal of Clinical Pharmacology, 2016. 56(2): p. 157-16

4、9.第一節(jié) 腫瘤微環(huán)境內(nèi)的免疫調(diào)節(jié)通路T 免細 疫胞 監(jiān)的 視Zou, W., J.D. Wolchok and L. Chen. Science Translational Medicine, 2016. 8(328): p. 328rv4-328rv4。PD-L1 與 TregsMichael Platten et al. Cancer Res 2012;72:5435-5440色氨酸的分解代謝IDO抑制劑與ICB組合Spranger, S., et al. J Immunother Cancer, 2014. 2: p. 3Th2細胞Coussens, L.M., L. Zitvogel

5、 and A.K. Palucka, Science, 2013. 339(6117): p. 286-291.Johanna A. Joyce, and Douglas T. Fearon. Science 2015;348:74-80第二節(jié) 表觀遺傳沉默趨化因子分泌 Cxcl9 和 Cxcl10Peng, D., et al. Nature, 2015. 527(7577): p. 249-253.第三節(jié) I 型干擾素信號Corrales, L. and T.F. Gajewski. Clinical Cancer Research, 2015. 21(21): p. 4774-4779.

6、I型干擾素激活與ICB組合Bald, T., et al. Cancer Discovery, 2014. 4(6): p. 674-687.第三章：展望組合治療的發(fā)展前景第一節(jié) 小鼠模型到臨床研究IDO抑制劑與ICBSTING激動劑與ICBI型干擾素與ICB其它I型干擾素的激活試劑與ICB？Spranger, S., et al. J Immunother Cancer, 2014. 2: p. 3Corrales, L. and T.F. Gajewski. Clinical Cancer Research, 2015. 21(21): p. 4774-4779.Bald, T., et

7、al. Cancer Discovery, 2014. 4(6): p. 674-687.第二節(jié) 減少免疫調(diào)節(jié)細胞Treg 與 ICBMenetrier-Caux, C., et al. Target Oncol, 2012. 7(1): p. 15-28.Zou, W., J.D. Wolchok and L. Chen. Science Translational Medicine, 2016. 8(328): p. 328rv4-328rv4。第二節(jié) 減少免疫調(diào)節(jié)細胞Th2 與 ICBCoussens, L.M., L. Zitvogel and A.K. Palucka, Scienc

8、e, 2013. 339(6117): p. 286-291.第三節(jié) 適用范圍Epigentic modulator 與 ICB Ovarian cancer Other cancer ?第四節(jié) 其它的思考控制副作用降低成本參考文獻 1.Pardoll, D.M., The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews Cancer, 2012. 12(4): p. 252-264. 2.Schumacher, T.N. and R.D. Schreiber, Neoantigens in canc

9、er immunotherapy. Science, 2015. 348(6230): p. 69-74. 3.Sharma, P. and J.P. Allison, The future of immune checkpoint therapy. Science, 2015. 348(6230): p. 56-61. 4.Buqu, A., et al., Trial Watch: Immunomodulatory monoclonal antibodies for oncological indications. OncoImmunology, 2015. 4(4): p. e10088

10、14. 5.Robert, C., et al., Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma. New England Journal of Medicine, 2011. 364(26): p. 2517-2526. 6.Fridman, W.H., et al., The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer, 2012. 12(4): p. 298-306. 7.Le

11、e, L., M. Gupta and S. Sahasranaman, Immune Checkpoint inhibitors: An introduction to the next-generation cancer immunotherapy. The Journal of Clinical Pharmacology, 2016. 56(2): p. 157-169. 8.Zou, W., J.D. Wolchok and L. Chen, PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms,

12、response biomarkers, and combinations. Science Translational Medicine, 2016. 8(328): p. 328rv4-328rv4.參考文獻9.Platten, M., W. Wick and B.J. Van den Eynde, Tryptophan Catabolism in Cancer: Beyond IDO and Tryptophan Depletion. Cancer Research, 2012. 72(21): p. 5435-5440.10.Spranger, S., et al., Mechanis

13、m of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. J Immunother Cancer, 2014. 2: p. 3.11.Coussens, L.M., L. Zitvogel and A.K. Palucka, Neutralizing Tumor-Promoting

14、 Chronic Inflammation: A Magic Bullet? Science, 2013. 339(6117): p. 286-291.12.Peng, D., et al., Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature, 2015. 527(7577): p. 249-253.13.Corrales, L. and T.F. Gajewski, Molecular Pathways: Targeting the Stimulator of Interferon Genes (STING) in the Immunotherapy of Cancer. Clinical Cancer Research, 2015. 21(21): p. 4774-4779.14.Bald, T., et al., Immun