DataSheet_1_Neoadjuvant Chemoradiotherapy Changes the Landscape of Soluble Immune Checkpoint Molecules in Patients With Locally Advanced Rectal Cancer.docx

BackgroundWe aimed to investigate clinical implications of specific soluble immune checkpoint molecules (sICMs) in locally advanced rectal cancer (LARC) patients treated with neoadjuvant chemoradiotherapy (nCRT).
MethodsWe prospectively enrolled 30 LARC patients treated with nCRT and collected blood samples from them before, during, and after nCRT for prospective studies. Immune checkpoints often refer to T cell surface molecules influencing the immune response. Immune checkpoints, in the form of a soluble monomeric form, is widely present in blood. In the study, eight immune checkpoint-related plasma proteins, including programmed death-ligand 1 (PD-L1), CD80, CD86, CD28, CD27, glucocorticoid-induced tumor necrosis factor receptor (GITR), GITR ligand (GITRL), and inducible T-cell costimulator (ICOS), were measured using the Luminex platform. Two independent pathologists categorized patients as the good responders and the poor responders according to Dworak tumor regression grade (TRG).
ResultsOf the 30 patients, the levels of sPD-L1, sCD80, sCD86, sCD28, sGITR, sGITRL, sCD27, and sICOS decreased during nCRT (Pre-nCRT vs. During-nCRT, all p<0.05) but were restored after nCRT treatment (Pre-nCRT vs. Post-nCRT, all p>0.05). In the 14 good responders, the levels of sICMs, other than sGITR (p=0.081) and sGITRL (p=0.071), decreased significantly during nCRT (Pre-nCRT vs. During-nCRT, p<0.05), but they were all significantly increased after nCRT (During-nCRT vs. Post-nCRT, all p<0.05). In the 16 poor responders, only sCD80 was significantly reduced during nCRT (Pre-nCRT vs. During-nCRT, p<0.05), and none was significantly increased after nCRT (During-nCRT vs. Post-nCRT, all p<0.05). High levels of sICMs before nCRT were associated with poor response (all OR≥1). The Pre-model that incorporated the 8 sICMs before nCRT yielded a good predictive value (AUC, 0.848) and was identified as an independent predictor of treatment response (OR, 2.62; 95% CI, 1.11-6.18; p=0.027).
ConclusionOur results suggest chemoradiotherapy could influence the change of sPD-L1, sCD80, sCD86, sCD28, sGITR, sGITRL, sCD27, and sICOS in patients with LARC. The levels of the majority of soluble immune checkpoint molecules were reduced during nCRT and then restored at the end of nCRT, particularly in patients who responded well to nCRT. Combined baseline sICMs can be developed to predict treatment response.

研究背景：本研究旨在探讨特定可溶性免疫检查点分子（soluble immune checkpoint molecules, sICMs）在接受新辅助放化疗（neoadjuvant chemoradiotherapy, nCRT）的局部晚期直肠癌（locally advanced rectal cancer, LARC）患者中的临床意义。研究方法：本研究前瞻性纳入30例接受nCRT治疗的LARC患者，并在nCRT治疗前、治疗期间及治疗后采集其血液样本用于前瞻性研究。免疫检查点通常指影响免疫应答的T细胞表面分子，以可溶性单体形式存在的免疫检查点广泛分布于血液中。本研究采用Luminex平台检测了8种免疫检查点相关血浆蛋白，包括程序性死亡受体配体1（programmed death-ligand 1, PD-L1）、CD80、CD86、CD28、CD27、糖皮质激素诱导的肿瘤坏死因子受体（glucocorticoid-induced tumor necrosis factor receptor, GITR）、GITR配体（GITRL）及诱导性T细胞共刺激分子（inducible T-cell costimulator, ICOS）。两名独立病理学家根据Dworak肿瘤退缩分级（Dworak tumor regression grade, TRG）将患者分为良好应答者与不良应答者。研究结果：30例患者中，可溶性PD-L1（sPD-L1）、sCD80、sCD86、sCD28、sGITR、sGITRL、sCD27及sICOS的水平在nCRT治疗期间均有所下降（新辅助放化疗前vs. 治疗期间，所有p<0.05），但在治疗后恢复至基线水平（新辅助放化疗前vs. 治疗后，所有p>0.05）。在14例良好应答者中，除sGITR（p=0.081）与sGITRL（p=0.071）外，其余sICMs的水平在nCRT治疗期间均显著下降（新辅助放化疗前vs. 治疗期间，p<0.05），并在治疗后显著升高（治疗期间vs. 治疗后，所有p<0.05）。在16例不良应答者中，仅sCD80的水平在nCRT治疗期间显著下降（新辅助放化疗前vs. 治疗期间，p<0.05），且治疗后其水平均未出现显著升高（治疗期间vs. 治疗后，所有p<0.05）。nCRT治疗前高水平的sICMs与不良应答相关（所有优势比≥1）。纳入nCRT治疗前8种sICMs的基线模型展现出良好的预测价值（曲线下面积AUC=0.848），且被证实为治疗应答的独立预测因子（优势比OR=2.62，95%置信区间CI=1.11~6.18，p=0.027）。研究结论：本研究结果表明，放化疗可影响LARC患者体内sPD-L1、sCD80、sCD86、sCD28、sGITR、sGITRL、sCD27及sICOS的水平变化。大多数可溶性免疫检查点分子的水平在nCRT治疗期间降低，并在治疗结束后恢复至基线水平，这一现象在nCRT应答良好的患者中尤为显著。联合检测基线sICMs可用于构建治疗应答预测模型。