Department of Gastroenterological Surgery, Cancer Institute Hospital, Tokyo, Japan.
Cancer Precision Medicine Centre, Tokyo, Japan.
Br J Surg. 2019 Sep;106(10):1381-1392. doi: 10.1002/bjs.11179. Epub 2019 Jun 13.
Accumulating evidence suggests that radiotherapy success has an immune-associated component. The immunogenomic profiles associated with responses to chemoradiotherapy (CRT) were assessed in patients with locally advanced rectal cancer in this study.
CD8+ tumour-infiltrating lymphocyte (TIL) and stromal lymphocyte densities were assessed by immunohistochemistry using pretreatment biopsies from patients with advanced rectal cancer who had preoperative CRT. Whole-exome sequencing and gene expression microarray analysis were conducted to investigate the genomic properties associated with the response to CRT and CD8+ TIL density. Response to CRT was determined based on Dworak tumour regression grade (TRG); tumours with complete (TRG 4) or near-complete (TRG 3) regression were grouped as good responders, and those with TRG 1 as non-responders.
Immunohistochemical examinations (275 patients) showed that pre-CRT CD8+ TIL density was associated with better response to CRT and improved recurrence-free survival, whereas pre-CRT stromal CD8+ cell density was not associated with either response to CRT or recurrence-free survival. Whole-exome sequencing (74 patients) showed that the numbers of single-nucleotide variations (SNVs) and neoantigens predicted from SNVs were higher in good responders than in non-responders, and these correlated positively with CD8+ TIL density (r = 0·315 and r = 0·334 respectively). Gene expression microarray (90 patients) showed that CD8A expression correlated positively with the expression of programmed cell death 1 (PDCD1) (r = 0·264) and lymphocyte-activation gene 3 (LAG3) (r = 0·507).
Pre-CRT neoantigen-specific CD8+ T cell priming may be a key event in CRT responses where immune checkpoint molecules could be useful targets to enhance tumour regression.
越来越多的证据表明，放射治疗的成功与免疫有关。本研究评估了局部晚期直肠癌患者接受放化疗（CRT）后与免疫相关的基因谱。
采用免疫组化法检测晚期直肠癌患者术前 CRT 前活检标本中 CD8+肿瘤浸润淋巴细胞（TIL）和基质淋巴细胞密度。采用全外显子测序和基因表达微阵列分析方法，研究与 CRT 反应和 CD8+TIL 密度相关的基因组特性。根据 Dworak 肿瘤消退分级（TRG）判断 CRT 反应：完全（TRG4）或接近完全（TRG3）消退的肿瘤归为应答良好组，TRG1 为无应答组。
免疫组化检查（275 例患者）显示，CRT 前 CD8+TIL 密度与 CRT 反应良好和无复发生存率提高相关，而 CRT 前基质 CD8+细胞密度与 CRT 反应或无复发生存率无关。全外显子测序（74 例患者）显示，应答良好组的单核苷酸变异（SNV）数量和预测的新抗原数量高于无应答组，且与 CD8+TIL 密度呈正相关（r 值分别为 0.315 和 0.334）。基因表达微阵列（90 例患者）显示，CD8A 表达与程序性细胞死亡 1（PDCD1）（r 值为 0.264）和淋巴细胞激活基因 3（LAG3）（r 值为 0.507）表达呈正相关。
CRT 反应中，CRT 前新抗原特异性 CD8+T 细胞的初始激活可能是关键事件，免疫检查点分子可能是增强肿瘤消退的有用靶点。
