Background/Objectives:Recent clinical trials in breast cancer have demonstrated that some patients benefit from immune checkpoint blockade, though better predictive markers are needed. The accumulation of the immunomodulatory matrix proteoglycan versican (VCAN) can predict the exclusion of CD8+tumor-infiltrating lymphocytes (TILs) in some settings and, thus, is evaluated in breast cancer here.Methods:A total of 230 breast cancers were analyzed for VCAN accumulation, VCAN proteolysis, and CD8+TILs. CD8+TILs were categorized based on their localization in the tumor epithelial or stromal compartments.Results:VCAN accumulation was detected in 90% of breast cancers, more commonly in ER+ tumors (93% vs. 77%;p< 0.001). MCF7 cells treated with estrogen upregulate VCAN without an enhanced expression of ADAMTS-proteases. VCAN-undetectable tumors demonstrate greater CD8+TILs compared to VCAN-detectable tumors (p= 0.012). CD8+T cells within TNBC tumors with high VCAN proteolysis infiltrated the epithelial compartment more often than in tumors with low VCAN proteolysis (91% vs. 42% respectively;p= 0.008). In the TCGA cohort, a strong inverse correlation between CD8A and VCAN expression was observed across subtypes.Conclusions:VCAN accumulation correlates with the exclusion of CD8+TILs across subtypes of breast cancer, warranting further validation of VCAN accumulation and proteolysis as predictive biomarkers for breast cancer immunotherapy.
背景/目的：近期乳腺癌临床试验表明，部分患者可从免疫检查点阻断治疗中获益，但仍需更优的预测标志物。免疫调节性基质蛋白聚糖多能蛋白聚糖（VCAN）的积聚在某些情况下可预测CD8+肿瘤浸润淋巴细胞（TILs）的排斥现象，本研究就此在乳腺癌中进行评估。方法：对230例乳腺癌样本进行VCAN积聚、VCAN蛋白水解及CD8+TILs分析，并根据CD8+TILs在肿瘤上皮或基质区域的定位进行分类。结果：90%的乳腺癌样本检测到VCAN积聚，其中雌激素受体阳性肿瘤更为常见（93% vs. 77%；p<0.001）。经雌激素处理的MCF7细胞会上调VCAN表达，但未增强ADAMTS蛋白酶表达。与可检测到VCAN的肿瘤相比，未检测到VCAN的肿瘤具有更多CD8+TILs（p=0.012）。在高VCAN蛋白水解的三阴性乳腺癌中，CD8+T细胞浸润上皮区域的频率显著高于低VCAN蛋白水解肿瘤（分别为91% vs. 42%；p=0.008）。在TCGA队列中，各亚型均观察到CD8A与VCAN表达呈强负相关。结论：VCAN积聚与各亚型乳腺癌中CD8+TILs的排斥现象相关，这支持将VCAN积聚及其蛋白水解作用作为乳腺癌免疫治疗的预测生物标志物进行进一步验证。
肿瘤(癌症)患者之家