Lee Hee Jin, Kim Joo Young, Song In Hye, Park In Ah, Yu Jong Han, Ahn Jin-Hee, Gong Gyungyub
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Department of Pathology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea.
Virchows Arch. 2015 Dec;467(6):701-709. doi: 10.1007/s00428-015-1861-1. Epub 2015 Oct 7.
Although the prognostic and predictive significance of tumor-infiltrating lymphocytes (TILs) in HER2-positive breast cancers has been established, the drivers of TIL influx remain unclear. We tested whether potential triggers for this response could include high mobility group B1 and N1 (HMGB1 and HMGN1) proteins, which are immunogenic damage-associated molecular pattern molecules. We evaluated TILs and the immunohistochemical expression of HMGB1 and HMGN1 in 447 HER2-positive breast cancer tissues. Normal luminal cells exhibited nuclear expression of HMGB1 and HMBN1. The nuclear and cytoplasmic expression levels of HMG proteins showed a significant inverse correlation (rho = -0.150, p = 0.001 for HMGB1; rho = -0.247, p < 0.001 for HMGN1). Low levels of HMGB1 and HMGN1 nuclear expression were identified in 185 (41.4 %) and 208 (46.5 %) cases, respectively. High levels of cytoplasmic HMGB1 and HMGN1 expression were identified in 107 (23.9 %) and 49 (11.0 %) cases, respectively. High cytoplasmic expression of HMG proteins was significantly associated with a high histological grade, high levels of TILs, peritumoral lymphocytic infiltration, and tertiary lymphoid structures in HER2-positive breast cancer tissues. Tumors with low levels of cytoplasmic HMGB1 and HMGN1 showed significantly lower levels of TILs than those with high levels of each or both HMG proteins. However, the nuclear or cytoplasmic expression of either HMG protein was not found to be significantly associated with survival. High levels of cytoplasmic HMGB1 and HMGN1 protein expression correlated with high levels of TILs in HER2-positive breast cancers. The manipulation of HMGB1 and HMGN1 could represent an immunotherapeutic approach to promote TIL influx into a tumor.
尽管肿瘤浸润淋巴细胞（TILs）在HER2阳性乳腺癌中的预后和预测意义已经明确，但TILs流入的驱动因素仍不清楚。我们测试了这种反应的潜在触发因素是否可能包括高迁移率族蛋白B1和N1（HMGB1和HMGN1），它们是具有免疫原性的损伤相关分子模式分子。我们评估了447例HER2阳性乳腺癌组织中TILs以及HMGB1和HMGN1的免疫组化表达。正常管腔细胞表现出HMGB1和HMBN1的核表达。HMG蛋白的核表达和细胞质表达水平呈显著负相关（HMGB1：rho = -0.150，p = 0.001；HMGN1：rho = -0.247，p < 0.001）。分别在185例（41.4%）和208例（46.5%）病例中检测到低水平的HMGB1和HMGN1核表达。分别在107例（23.9%）和49例（11.0%）病例中检测到高水平的细胞质HMGB1和HMGN1表达。HMG蛋白的高细胞质表达与HER2阳性乳腺癌组织中的高组织学分级、高水平的TILs、肿瘤周围淋巴细胞浸润和三级淋巴结构显著相关。细胞质HMGB1和HMGN1水平低的肿瘤显示出的TILs水平明显低于HMG蛋白水平高的肿瘤或两者水平都高的肿瘤。然而，未发现任何一种HMG蛋白的核表达或细胞质表达与生存显著相关。HER2阳性乳腺癌中高水平的细胞质HMGB1和HMGN1蛋白表达与高水平的TILs相关。对HMGB1和HMGN1的调控可能代表一种促进TILs流入肿瘤的免疫治疗方法。
