Tumor-draining lymph node is important for a robust abscopal effect stimulated by radiotherapy.
Tumor-draining lymph node is important for a robust abscopal effect stimulated by radiotherapy.
复制标题
DOI：
10.1136/jitc-2020-000867
复制
发表时间：
2020-10
影响因子：
10.9
通讯作者：
Khan MK
中科院分区：
文献类型：
--
作者：
Buchwald ZS;Nasti TH;Lee J;Eberhardt CS;Wieland A;Im SJ;Lawson D;Curran W;Ahmed R;Khan MK
放射治疗（RT）已被证明可以刺激受照射肿瘤以及未受照射的远端部位的抗肿瘤免疫应答（远位效应）。先前的研究已经证明了肿瘤引流淋巴结（LN）在介导抗程序性死亡-1（PD-1）/程序性死亡配体-1（PD-L1）刺激的抗肿瘤免疫应答中的作用。在这里，我们调查是否LN也是重要的，在介导的RT单独刺激远位反应。我们使用双侧注射的皮下改良B16 F10侧腹肿瘤模型。我们的B16 F10细胞系具有插入的病毒糖蛋白，其促进了肿瘤特异性T细胞的鉴定。RT仅针对一侧腹侧肿瘤或针对一侧腹侧肿瘤和肿瘤引流LN。我们通过肿瘤生长测量和肿瘤浸润和LN T细胞的流式细胞术来评估反应。我们发现，局部肿瘤照射改善了远处肿瘤控制（远位效应）。CD 8 + T细胞的耗竭显著降低了这种远位反应。我们之前已经证明，在慢性淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染中，PD-1/L1阻断后的T细胞增殖爆发是由“干细胞样”CD 8 + T细胞亚群提供的，然后分化为终末分化的效应物。这些终末分化的效应物具有在PD-1/L1阻断后杀死病毒感染或肿瘤细胞的潜力。在慢性LCMV感染中，干细胞样CD 8 + T细胞仅见于次级淋巴器官。同样，我们在肿瘤引流LN中发现这些细胞以高频存在，但在肿瘤内以低频存在。RT对该T细胞亚群的影响未知。有趣的是，肿瘤照射刺激LN中的总CD 8+和干细胞样CD 8 + T细胞增殖。当LN和肿瘤被RT靶向时，远位效应降低，并且我们发现在照射和未照射的肿瘤中总肿瘤特异性CD 8 + T细胞和干细胞样CD 8 + T细胞的数量同时减少。这些相关的结果表明，肿瘤引流LN可能是一个重要的介质的远端效应作为干细胞样CD 8 + T细胞库，干细胞样T细胞扩增的网站，并从他们可以填充肿瘤。
Radiotherapy (RT) has been shown to stimulate an antitumor immune response in irradiated tumors as well as unirradiated distant sites (abscopal effect). Previous studies have demonstrated a role for the tumor-draining lymph node (LN) in mediating an anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) stimulated antitumor immune response. Here, we investigated whether the LN is also important in mediating a RT alone stimulated abscopal response. We used a subcutaneous modified B16F10 flank tumor model injected bilaterally. Our B16F10 cell line has an inserted viral glycoprotein which facilitated identification of tumor-specific T-cells. RT was directed at one flank tumor alone or one flank tumor and the tumor-draining LN. We evaluated response by tumor growth measurements and flow cytometry of both tumor-infiltrating and LN T-cells. We show that local tumor irradiation improves distant tumor control (abscopal effect). Depletion of CD8+ T-cells significantly reduced this abscopal response. We have previously shown, in a chronic lymphocytic choriomeningitis virus (LCMV) infection, that the T-cell proliferative burst following blockade of PD-1/L1 is provided by a ‘stem-like’ CD8+ T-cell subset which then differentiate into terminally differentiated effectors. These terminally differentiated effectors have the potential to kill virally infected or tumor cells following PD-1/L1 blockade. In the chronic LCMV infection, stem-like CD8+ T-cells were found exclusively in secondary lymphoid organs. Similarly, here we found these cells at high frequencies in the tumor-draining LN, but at low frequencies within the tumor. The effect of RT on this T-cell subset in unknown. Interestingly, tumor irradiation stimulated total CD8+ and stem-like CD8+ T-cell proliferation in the LN. When the LN and the tumor were then targeted with RT, the abscopal effect was reduced, and we found a concomitant reduction in the number of total tumor-specific CD8+ T-cells and stem-like CD8+ T-cells in both the irradiated and unirradiated tumor. These correlative results suggest the tumor-draining LN may be an important mediator of the abscopal effect by serving as a stem-like CD8+ T-cell reservoir, a site for stem-like T-cell expansion, and a site from which they can populate the tumor.
登录
查看更多内容
影响因子：
11.2
作者：
Burnette BC;Liang H;Lee Y;Chlewicki L;Khodarev NN;Weichselbaum RR;Fu YX;Auh SL
通讯作者：
Auh SL
影响因子：
64.8
作者：
Im SJ;Hashimoto M;Gerner MY;Lee J;Kissick HT;Burger MC;Shan Q;Hale JS;Lee J;Nasti TH;Sharpe AH;Freeman GJ;Germain RN;Nakaya HI;Xue HH;Ahmed R
通讯作者：
Ahmed R
DOI：
10.1158/1078-0432.ccr-09-0265
发表时间：
2009-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Dewan MZ;Galloway AE;Kawashima N;Dewyngaert JK;Babb JS;Formenti SC;Demaria S
通讯作者：
Demaria S
DOI：
10.1056/nejmoa1613210
发表时间：
2017-06-08
期刊：
The New England journal of medicine
影响因子：
--
作者：
Faries MB;Thompson JF;Cochran AJ;Andtbacka RH;Mozzillo N;Zager JS;Jahkola T;Bowles TL;Testori A;Beitsch PD;Hoekstra HJ;Moncrieff M;Ingvar C;Wouters MWJM;Sabel MS;Levine EA;Agnese D;Henderson M;Dummer R;Rossi CR;Neves RI;Trocha SD;Wright F;Byrd DR;Matter M;Hsueh E;MacKenzie-Ross A;Johnson DB;Terheyden P;Berger AC;Huston TL;Wayne JD;Smithers BM;Neuman HB;Schneebaum S;Gershenwald JE;Ariyan CE;Desai DC;Jacobs L;McMasters KM;Gesierich A;Hersey P;Bines SD;Kane JM;Barth RJ;McKinnon G;Farma JM;Schultz E;Vidal-Sicart S;Hoefer RA;Lewis JM;Scheri R;Kelley MC;Nieweg OE;Noyes RD;Hoon DSB;Wang HJ;Elashoff DA;Elashoff RM
通讯作者：
Elashoff RM
影响因子：
8
作者：
Fransen, Marieke F.;Schoonderwoerd, Mark;Ossendorp, Ferry
通讯作者：
Ossendorp, Ferry