title: 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.
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.
authors.affiliation: Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München (TUM) , München , Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Gunther
authors.affiliation: Department of Radiation Oncology, Martin Luther University Halle-Wittenberg , Halle (Saale) , Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Ostheimer
authors.affiliation: Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München (TUM) , München , Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stangl
authors.affiliation: Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München (TUM) , München , Germany.
authors.forename: Hanno M
authors.initials: HM
authors.lastname: Specht
authors.affiliation: Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München (TUM) , München , Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Mozes
authors.affiliation: Department of Pathology, Klinikum rechts der Isar, Technische Universität München (TUM) , München , Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Jesinghaus
authors.affiliation: Department of Radiation Oncology, Martin Luther University Halle-Wittenberg , Halle (Saale) , Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Vordermark
authors.affiliation: Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München (TUM) , München , Germany ; Department of Innovative Radiotherapy (iRT), Helmholtz Zentrum München , Oberschleißheim , Germany ; Department of Radiation Sciences (DRS), Helmholtz Zentrum München , Oberschleißheim , Germany.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Combs
authors.affiliation: Pulmonary Division, 1 Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München (TUM) , München , Germany.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Peltz
authors.affiliation: Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München (TUM) , München , Germany.
authors.forename: Max P
authors.initials: MP
authors.lastname: Jung
authors.affiliation: Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München (TUM) , München , Germany ; Department of Innovative Radiotherapy (iRT), Helmholtz Zentrum München , Oberschleißheim , Germany ; Department of Radiation Sciences (DRS), Helmholtz Zentrum München , Oberschleißheim , Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Multhoff
keywords: NSCLC; biological; biomarker; gross tumor volume; heat-shock protein 70; immune responses; lymphocytes; tumor markers