Spatial Distribution and Predictive Significance of Dendritic Cells and Macrophages in Esophageal Cancer Treated With Combined Chemoradiotherapy and PD-1 Blockade.
Spatial Distribution and Predictive Significance of Dendritic Cells and Macrophages in Esophageal Cancer Treated With Combined Chemoradiotherapy and PD-1 Blockade.
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放化疗联合PD-1阻断治疗食管癌树突状细胞和巨噬细胞的空间分布及其预测意义
DOI：
10.3389/fimmu.2021.786429
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发表时间：
2021
影响因子：
7.3
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Ma X;Guo Z;Wei X;Zhao G;Han D;Zhang T;Chen X;Cao F;Dong J;Zhao L;Yuan Z;Wang P;Pang Q;Yan C;Zhang W
第一项一线放化疗联合PD-1阻断剂的临床研究（NCT 03671265）显示，局部晚期食管鳞状细胞癌（ESCC）的治疗结局很有希望。然而，部分患者对联合治疗无反应。树突状细胞（DC）和巨噬细胞在这种联合治疗中的作用仍然知之甚少。方法采用多重免疫荧光法检测36例Ib期临床试验（NCT 03671265）患者术前和放疗后（40戈伊放疗后）的配对肿瘤活检标本中CD 11 c + DC、CD 68+巨噬细胞及其PD-L1-或PD-L1+亚群。我们在基线肿瘤活检（n = 14）中应用全外显子组测序来估计肿瘤突变负荷（TMB）。我们动态研究了放化疗联合PD-1阻断下DC和巨噬细胞的空间分布，并评估了它们的空间分布与联合治疗结果和TMB之间的相关性。结果PD-L1- DCs和巨噬细胞在基线肿瘤区室而非间质区室中的高百分比预测OS和PFS的改善。放化疗联合PD-1阻断可促进DC和巨噬细胞向肿瘤细胞迁移。在联合治疗期间，PD-L1-肿瘤细胞最靠近PD-L1-DC和巨噬细胞，而PD-L1+肿瘤细胞靠近PD-L1+ DC和巨噬细胞。高TMB与肿瘤细胞到DC和巨噬细胞的距离较短密切相关。在联合治疗期间，PD-L1+肿瘤细胞与PD-L1+ DC或PD-L1-巨噬细胞之间的距离越短，OS越好。在联合治疗期间，PD-L1-肿瘤细胞与PD-L1-巨噬细胞之间的距离越短，OS和PFS越长。结论PD-L1-或PD-L1+ DCs和巨噬细胞在食管鳞癌中具有明显的空间分布。肿瘤细胞和这些抗原呈递细胞（APC）之间的近距离对于ESCC患者中放化疗联合PD-1阻断的临床结果至关重要。我们的研究结果强调了APC的空间模式在放化疗联合免疫治疗中的预测潜力，并揭示了APC参与放化疗诱导的ESCC抗肿瘤免疫应答的潜在机制。
Background The first clinical study (NCT03671265) of first-line chemoradiotherapy combined with PD-1 blockade showed promising treatment outcomes in locally advanced esophageal squamous cell carcinoma (ESCC). However, partial patients did not respond to the combination treatment. The roles of dendritic cells (DCs) and macrophages in this combination treatment remain poorly understood. Methods We performed multiplexed immunofluorescence method to identify CD11c+ DCs, CD68+ macrophages, and their PD-L1- or PD-L1+ subpopulations in paired tumor biopsies (n = 36) collected at baseline and during the combination treatment (after radiation, 40 Gy) from the phase Ib trial (NCT03671265). We applied whole exome sequencing in the baseline tumor biopsies (n = 14) to estimate tumor mutation burden (TMB). We dynamically investigated the spatial distribution of DCs and macrophages under chemoradiotherapy combined with PD-1 blockade, and evaluated the association between their spatial distribution and combination outcome, and TMB. Results The results showed that high percentages of PD-L1- DCs and macrophages in the baseline tumor compartment, but not in the stromal compartment, predicted improved OS and PFS. Chemoradiotherapy combined with PD-1 blockade promoted DCs and macrophages to migrate closer to tumor cells. During combination treatment, PD-L1- tumor cells were nearest to PD-L1- DCs and macrophages, while PD-L1+ tumor cells were next to PD-L1+ DCs and macrophages. High TMB was closely associated with a shorter distance from tumor cells to DCs and macrophages. Shorter distance between PD-L1+ tumor cells and PD-L1+ DCs or PD-L1- macrophages during the combination was correlated with better OS. Shorter distance between PD-L1- tumor cells and PD-L1- macrophages during combination was associated with both longer OS and PFS. Conclusions PD-L1- or PD-L1+ DCs and macrophages exhibit distinct spatial distribution in ESCC. The close distance between tumor cells and these antigen-presenting cells (APCs) is critical to the clinical outcome in chemoradiotherapy combined with PD-1 blockade in ESCC patients. Our results highlight the predictive potential of spatial patterns of APCs in chemoradiotherapy combined with immunotherapy and reveal the underlying mechanism of APCs participating in chemoradiotherapy-induced antitumor immune response in ESCC.
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影响因子：
6.4
作者：
Collin M;Bigley V
通讯作者：
Bigley V
食管鳞状细胞癌的空间瘤内异质性和时间克隆进化
影响因子：
30.8
作者：
Hao, Jia-Jie;Lin, De-Chen;Dinh, Huy Q.;Mayakonda, Anand;Jiang, Yan-Yi;Chang, Chen;Jiang, Ye;Lu, Chen-Chen;Shi, Zhi-Zhou;Xu, Xin;Zhang, Yu;Cai, Yan;Wang, Jin-Wu;Zhan, Qi-Min;Wei, Wen-Qiang;Berrnan, Benjamin P.;Wang, Ming-Rong;Koeffler, H. Phillip
通讯作者：
Koeffler, H. Phillip
影响因子：
6.4
作者：
Lundgren, Sebastian;Elebro, Jacob;Mezheyeuski, Artur
通讯作者：
Mezheyeuski, Artur
影响因子：
51.1
作者：
Noordman, Bo Jan;Spaander, Manon C. W.;van Lanschot, J. Jan B.
通讯作者：
van Lanschot, J. Jan B.
影响因子：
10.3
作者：
Bareche, Yacine;Buisseret, Laurence;Sotiriou, Christos
通讯作者：
Sotiriou, Christos