Xin Haisong, Zhou Chaoxi, Wang Guanglin, Liu Yan, Zhang Juan, Liu Youqiang, Li Baokun, Zhang Jianfeng, Su Mingming, Li Zhihan, Wang Guiying
Department of General Surgery, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, People's Republic of China.
Department of Endocrinology, Hebei Medical University Third Affiliated Hospital, Shijiazhuang, Hebei, People's Republic of China.
Heliyon. 2023 Jan 16;9(2):e13048. doi: 10.1016/j.heliyon.2023.e13048. eCollection 2023 Feb.
In recent years, immune checkpoint inhibitors have become a major therapeutic method for the treatment of metastatic colorectal cancer (mCRC). Growing evidence indicates that tumour-infiltrating lymphocytes (TILs) in the tumour microenvironment are a prerequisite for the effectiveness of PD-1/PD-L1 blockade therapy. In this study, we aimed to compare PD-L1 expression and cluster of differentiation 4 (CD4) and CD8 TIL infiltration in primary tumours and paired metastases.
Altogether, 111 patients with mCRC who underwent surgery at our hospital were included. PD-L1, CD4, and CD8 expression were detected by immunohistochemistry in a tissue microarray. PD-L1 expression was assessed using the combined positivity score (CPS), and a score ≥1 was judged as positive. The area proportion of TILs with positive staining ≥10% was classified as "high", while <10% was classified as "low".
We observed the discordance of PD-L1 expression between primary tumours and paired metastases in 35/111 (31.5%) patients (κ = 0.137, P = 0.142). This heterogeneity was significantly correlated with discordance of CD8 TIL infiltration between primary tumours and paired metastases (P = 0.003). Compared with corresponding colorectal cancer tumours, lung metastases showed more CD8 TIL infiltration (P = 0.022, median: 8.5% vs. 5.0%), whereas liver metastases exhibited less CD8 TIL infiltration (P = 0.028, median: 3.0% vs. 5.0%). Area proportion of CD4 and CD8 TIL infiltration in lung metastases were all higher than those in liver metastases (P = 0.005, median: 15.0% vs. 9.0%; P = 0.001, median: 8.5% vs. 3.0%). Compared with p MMR (MSI-L/MS-S) subgroup, area proportion of CD8 TIL infiltration in primary tumours and CD4, CD8 TIL infiltration in paired metastases were all higher in d MMR (MSI-H) group (P = 0.026, median: 15.0% vs 5.0%; P = 0.039, median: 15.0% vs 9.0%; P = 0.015, median: 15.0% vs 5.0%). Preoperative chemo/radiotherapy may increase CD8 TIL infiltration in primary tumours (P = 0.045, median: 10.0% vs. 5.0%). CD8 TIL infiltration in primary tumours was an independent predictive factor for overall survival (HR 0.28, 95% CI 0.09-0.93, P = 0.038).
Heterogeneity in PD-L1 expression and CD8 TIL infiltration was found between primary tumours and paired metastases in mCRC. CD8 TIL infiltration in primary tumours could independently forecast the overall survival of patients with mCRC.
近年来，免疫检查点抑制剂已成为治疗转移性结直肠癌（mCRC）的主要治疗方法。越来越多的证据表明，肿瘤微环境中的肿瘤浸润淋巴细胞（TILs）是PD-1/PD-L1阻断疗法有效性的先决条件。在本研究中，我们旨在比较原发性肿瘤和配对转移灶中PD-L1的表达以及分化簇4（CD4）和CD8 TIL浸润情况。
共纳入111例在我院接受手术的mCRC患者。通过免疫组织化学在组织芯片中检测PD-L1、CD4和CD8的表达。使用联合阳性评分（CPS）评估PD-L1表达，评分≥1判定为阳性。TILs阳性染色面积比例≥10%分类为“高”，<10%分类为“低”。
我们观察到35/111（31.5%）例患者原发性肿瘤和配对转移灶之间PD-L1表达不一致（κ = 0.137，P = 0.142）。这种异质性与原发性肿瘤和配对转移灶之间CD8 TIL浸润的不一致显著相关（P = 0.003）。与相应的结直肠癌肿瘤相比，肺转移灶显示更多的CD8 TIL浸润（P = 0.022，中位数：8.5%对5.0%），而肝转移灶CD8 TIL浸润较少（P = 0.028，中位数：3.0%对5.0%）。肺转移灶中CD4和CD8 TIL浸润的面积比例均高于肝转移灶（P = 0.005，中位数：15.0%对9.0%；P = 0.001，中位数：8.5%对3.0%）。与错配修复功能正常（pMMR，微卫星稳定/微卫星高度稳定）亚组相比，错配修复缺陷（dMMR，微卫星高度不稳定）组原发性肿瘤中CD8 TIL浸润的面积比例以及配对转移灶中CD4、CD8 TIL浸润的面积比例均更高（P = 0.026，中位数：15.0%对5.0%；P = 0.039，中位数：15.0%对9.0%；P = 0.015，中位数：15.0%对5.0%）。术前化疗/放疗可能增加原发性肿瘤中CD8 TIL浸润（P = 0.045，中位数：10.0%对5.0%）。原发性肿瘤中CD8 TIL浸润是总生存的独立预测因素（风险比0.28，95%置信区间0.09 - 0.93，P = 0.038）。
在mCRC的原发性肿瘤和配对转移灶之间发现了PD-L1表达和CD8 TIL浸润的异质性。原发性肿瘤中CD8 TIL浸润可独立预测mCRC患者的总生存。
