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.

Sophie Gunther,Moritz Jesinghaus,Gabriele Multhoff,Stefan Stangl,Friedhelm Peltz,Hanno M Specht,Stephanie E Combs,Petra Mozes,Dirk Vordermark,Christian Ostheimer,Max P Jung

doi:10.3389/fimmu.2015.00556

Abstract

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.

Highlights

According to recent statistics, lung cancer is still among the most frequent causes of cancer-related deaths and the second most common cancer in both men and women in Western societies [1]
For a better understanding of this duality of mHsp70, we addressed the question whether serum Heat-shock protein 70 (Hsp70) levels are associated with clinical parameters, such as gross tumor volume (GTV) at diagnosis and after radiochemotherapy (RCT), and whether serum Hsp70 levels can have impact on the immune phenotype of squamous cell and adeno nonsmall cell lung cancer (NSCLC) [18]
We could show that Hsp70 detected by the lipHsp70 ELISA can serve as a tumor biomarker in liquid biopsies of patients with squamous cell and adeno NSCLC

Summary

Introduction

Lung cancer is still among the most frequent causes of cancer-related deaths and the second most common cancer in both men and women in Western societies [1]. According to the GLOBOCAN report 2000 [3], the incidence of lung cancer worldwide is 1,238,900 with a mortality of 1,103,100 and a 5-year prevalence of 1,394,400. One reason for this high mortality is that patients with lung cancer are frequently diagnosed in advanced tumor stages since the symptoms, such as dyspnea, coughing, or chest pain, are quite unspecific for a long period of time [4].

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