Emmerich Philip B, Qyli Tonela, Johnson Katherine A, Chaudhuri Somak, Clark Kristen M, Verhagen Nathaniel B, Depke Mitchell G, Clipson Linda, Pasch Cheri A, Papadas Athanasios, Burkard Mark E, Wisinski Kari B, McGregor Stephanie M, Asimakopoulos Fotis, Deming Dustin A
Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
Cellular and Molecular Pathology Graduate Program, Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
Cancers (Basel). 2025 Apr 25;17(9):1435. doi: 10.3390/cancers17091435.
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. 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. VCAN accumulation was detected in 90% of breast cancers, more commonly in ER+ tumors (93% vs. 77%; < 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 ( = 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; = 0.008). In the TCGA cohort, a strong inverse correlation between CD8A and VCAN expression was observed across subtypes. 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.
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，不过仍需要更好的预测标志物。免疫调节性基质蛋白聚糖多功能蛋白聚糖（VCAN）的积累在某些情况下可预测CD8肿瘤浸润淋巴细胞（TILs）的排除，因此本文对其在乳腺癌中的情况进行了评估。对230例乳腺癌进行了VCAN积累、VCAN蛋白水解及CD8 TILs分析。CD8 TILs根据其在肿瘤上皮或基质区室中的定位进行分类。90%的乳腺癌中检测到VCAN积累，更常见于雌激素受体阳性（ER+）肿瘤（93%对77%；P<0.001）。用雌激素处理的MCF7细胞上调VCAN，而ADAMTS蛋白酶表达未增强。与可检测到VCAN的肿瘤相比，未检测到VCAN的肿瘤显示出更多的CD8 TILs（P=0.012）。VCAN蛋白水解程度高的三阴性乳腺癌（TNBC）肿瘤中的CD8 T细胞比VCAN蛋白水解程度低的肿瘤更常浸润上皮区室（分别为91%对42%；P=0.008）。在癌症基因组图谱（TCGA）队列中，各亚型中均观察到CD8A与VCAN表达之间存在强烈的负相关。VCAN积累与乳腺癌各亚型中CD8 TILs的排除相关，有必要进一步验证VCAN积累和蛋白水解作为乳腺癌免疫治疗预测生物标志物的作用。
