1、Anti-VEGF/VEGFR2 axis enhances radio-resistance via regulatory T-cell depletion1.Radiation enhances regulatory T cell representation2.Treg contribute to the resistance of tumor to radiation3.VEGFA-VEGFR pathway blockade can inhibit regulatory T-cell proliferation4.Raising my hypothesis Contents1.Rad
2、iation enhances regulatory T cell representationHerrera FG,et al.CA Cancer J Clin.2016 Aug 29.Immune Mechanisms Triggered by Tumor IrradiationHerrera FG,et al.CA Cancer J Clin.2016 Aug 29.Radiotherapy Reprograms the Tumor MicroenvironmentReported Clinical Cases of Abscopal Effects of Radiotherapy in
3、 Combination With ImmunotherapyHerrera FG,et al.CA Cancer J Clin.2016 Aug 29.Treg cells increase temporarily after local irradiation.Kachikwu EL,et al.Int J Radiat Oncol Biol Phys.2011 Nov 15;81(4):1128-35.The radiation-induced increase in Treg cells is dose dependent.Kachikwu EL,et al.Int J Radiat
4、Oncol Biol Phys.2011 Nov 15;81(4):1128-35.Low radiation doses to the whole body reduced spleen size,weight,and cell numbers while increasing the proportion of splenic T regulatory(Treg)cells.Kachikwu EL,et al.Int J Radiat Oncol Biol Phys.2011 Nov 15;81(4):1128-35.Different responses of CD4+CD25high
5、T cells and CD4+CD25-T cells to irradiation in vitro.Qu Y,et al.Radiat Res.2010;173:148-157.Flow cytometry analysis of Bcl-2 expression in CD4+CD25high T cells and CD4+CD25-T cells.Qu Y,et al.Radiat Res.2010;173:148-157.Shimizu J,et al.Nat Immunol.2002 Feb;3(2):135-42.Price JG,et al.Nat Immunol.2015
6、 Oct;16(10):1060-8.Liu S,et al.Am J Cancer Res.2015 Oct 15;5(11):3276-85.2.Treg contribute to the resistance of tumor to radiationSchematic of the protocol for combination treatment of radiation and low-dose CTX or anti-CD25 mAbSon CH,et al.Int J Radiat Oncol Biol Phys.2015 Jun 1;92(2):390-8.Low-dos
7、e CTX or anti-CD25 mAb treatment significantly enhances the therapeutic efficacy of radiation therapySon CH,et al.Int J Radiat Oncol Biol Phys.2015 Jun 1;92(2):390-8.Low-dose CTX or anti-CD25 mAb treatment combined with radiation therapy significantly prolongs survival time.Son CH,et al.Int J Radiat
8、 Oncol Biol Phys.2015 Jun 1;92(2):390-8.Tregs interfere with irradiation-induced k1106 cell apoptosis.Li Q,et al.Cell Mol Immunol.2015;12:366-72.Liu S,et al.Am J Cancer Res.2015 Oct 15;5(11):3276-85.3.VEGFA-VEGFR pathway blockade can inhibit regulatory T-cell proliferationAnti-VEGF-A treatments sign
9、ificantly reduce Treg proportions and numbersTerme M,et al.Cancer Res.2013 Jan 15;73(2):539-49.Terme M,et al.Cancer Res.2013 Jan 15;73(2):539-49.Sunitinib treatments significantly reduce Treg proportions and numbersTerme M,et al.Cancer Res.2013 Jan 15;73(2):539-49.Sunitinib treatments significantly
10、reduce Treg proportions and numbersTregs proliferate in response to VEGF-A stimulation.Terme M,et al.Cancer Res.2013 Jan 15;73(2):539-49.Tregs in tumor-bearing mice express VEGF receptorsTerme M,et al.Cancer Res.2013 Jan 15;73(2):539-49.Tregs in tumor-bearing mice express VEGF receptors and their pr
11、oliferation is VEGFR-2dependent.Terme M,et al.Cancer Res.2013 Jan 15;73(2):539-49.Voron T,et al.Front Oncol.2014 Apr 2;4:70.4.Raising my hypothesis Tian S,et al.Cancer Sci.2011;102:137480.Anti-VEGF/VEGFR2 axis enhances Radio-resistance via regulatory T-cell depletion1 体内研究照射后及外周血、脾脏、引流淋巴结体内研究照射后及外周血
12、、脾脏、引流淋巴结Treg绝绝对含量及百分比对含量及百分比 2 检测荷瘤小鼠检测荷瘤小鼠Treg表达表达VEGFR2情况情况 3 加阿帕替尼后检测外周血、脾脏、引流淋巴结加阿帕替尼后检测外周血、脾脏、引流淋巴结Treg绝绝对含量及百分比对含量及百分比 4 体外研究阿帕替尼联合放疗对体外研究阿帕替尼联合放疗对Treg 功能的影响功能的影响 5 放疗和阿帕替尼联合方式：放疗和阿帕替尼联合方式：“时间窗时间窗”，续贯或同步：，续贯或同步：生存曲线生存曲线Experiment In vivo and vitroPatients enrolledRandomized1 week of Apatinib treatment RespondersNonresponders+RadiotherapyComparing their PFS,OSClinical trial
