Correlation of Hsp70 Serum Levels with Gross Tumor Volume and Composition of Lymphocyte Subpopulations in Patients with Squamous Cell and Adeno Non-Small Cell Lung Cancer.
Correlation of Hsp70 Serum Levels with Gross Tumor Volume and Composition of Lymphocyte Subpopulations in Patients with Squamous Cell and Adeno Non-Small Cell Lung Cancer.
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DOI：
10.3389/fimmu.2015.00556
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发表时间：
2015
影响因子：
7.3
通讯作者：
Multhoff G
中科院分区：
文献类型：
--
作者：
Gunther S;Ostheimer C;Stangl S;Specht HM;Mozes P;Jesinghaus M;Vordermark D;Combs SE;Peltz F;Jung MP;Multhoff G
热休克蛋白70（Heat-shock protein 70，Hsp 70）是一种存在于包括非小细胞肺癌（non-small cell lung cancer，NSCLC）在内的多种恶性肿瘤细胞的细胞膜上的蛋白质。一方面，膜（m）Hsp 70阳性表型与肿瘤的高侵袭性相关;另一方面，mHsp 70充当已经用Hsp 70-肽TKD加低剂量白细胞介素-2（TKD/IL-2）预刺激的自然杀伤（NK）细胞的靶标。活化后，NK细胞显示活化C型凝集素受体（如CD 94/NKG 2C、NKG 2D）和天然细胞毒性受体（NCR; NKp 44、NKp 46和NKp 30）的表达上调，从而获得杀死mHsp 70阳性肿瘤细胞的能力。关于这些结果，目前在TUM的一项概念验证II期临床试验中，在放化疗（RCT）后的鳞状细胞NSCLC患者中检测了离体TKD/IL-2刺激的自体NK细胞的疗效。入选标准为经组织学证实的IIIA/IIIB期不可切除NSCLC、RCT临床缓解和mHsp 70阳性肿瘤表型。使用lipHsp 70 ELISA测试确定患者血清中的mHsp 70状态，其能够定量脂质体和游离Hsp 70。鳞状细胞和腺癌NSCLC患者血清Hsp 70水平显著高于健康对照组。血清Hsp 70水平与大体肿瘤体积在腺和鳞状细胞NSCLC中显示出显著相关性。然而，仅在鳞状细胞肺癌患者中观察到与低血清Hsp 70水平相关的活化的CD 69 +/CD 94 + NK细胞的比率显著升高。这些数据可能提供了第一个提示，鳞状细胞NSCLC比腺NSCLC更具免疫原性。
Heat-shock protein 70 (Hsp70) is frequently found on the plasma membrane of a large number of malignant tumors including non-small cell lung cancer (NSCLC) and gets released into the blood circulation in lipid vesicles. On the one hand, a membrane (m)Hsp70-positive phenotype correlates with a high aggressiveness of the tumor; on the other hand, mHsp70 serves as a target for natural killer (NK) cells that had been pre-stimulated with Hsp70-peptide TKD plus low-dose interleukin-2 (TKD/IL-2). Following activation, NK cells show an up-regulated expression of activatory C-type lectin receptors, such as CD94/NKG2C, NKG2D, and natural cytotoxicity receptors (NCRs; NKp44, NKp46, and NKp30) and thereby gain the capacity to kill mHsp70-positive tumor cells. With respect to these results, the efficacy of ex vivo TKD/IL-2 stimulated, autologous NK cells is currently tested in a proof-of-concept phase II clinical trial in patients with squamous cell NSCLC after radiochemotherapy (RCT) at the TUM. Inclusion criteria are histological proven, non-resectable NSCLC in stage IIIA/IIIB, clinical responses to RCT and a mHsp70-positive tumor phenotype. The mHsp70 status is determined in the serum of patients using the lipHsp70 ELISA test, which enables the quantification of liposomal and free Hsp70. Squamous cell and adeno NSCLC patients had significantly higher serum Hsp70 levels than healthy controls. A significant correlation of serum Hsp70 levels with the gross tumor volume was shown for adeno and squamous cell NSCLC. However, significantly elevated ratios of activated CD69+/CD94+ NK cells that are associated with low serum Hsp70 levels were observed only in patients with squamous cell lung cancer. These data might provide a first hint that squamous cell NSCLC is more immunogenic than adeno NSCLC.