Abstract
Heat shock protein 70 (Hsp70) which is expressed on the plasma membrane of highly aggressive tumors including non-small cell lung carcinoma and glioblastoma multiforme serves as a target for Hsp70-targeting NK cells. Herein, we aimed to investigate the antitumor effects of a combined therapy consisting of ex vivo Hsp70-peptide TKD/IL-2-activated NK cells in combination with mouse/human anti-PD-1 antibody in a syngeneic glioblastoma and a xenograft lung cancer mouse model. Mice with membrane Hsp70 positive syngeneic GL261 glioblastoma or human xenograft A549 lung tumors were sham-treated with PBS or injected with ex vivo TKD/IL-2-activated mouse/human NK cells and mouse/human PD-1 antibody either as a single regimen or in combination. Tumor volume was assessed by MR scanning and tumor-infiltrating CD8+ T, NK, and PD-1+ cells were quantified by immunohistochemistry (IHC). We could show that the adoptive transfer of ex vivo TKD/IL-2-activated mouse NK cells or the inhibition of PD-1 resulted in tumor growth delay and an improved overall survival (OS) in a syngeneic glioblastoma mouse model. A combination of both therapies was well-tolerated and significantly more effective with respect to both outcome parameters than either of the single regimens. A combined treatment in a xenograft lung cancer model showed identical effects in immunodeficient mice bearing human lung cancer after adoptive transfer of TKD/IL-2-activated human effector cells and a human PD-1 antibody. Tumor control was associated with a massive infiltration with CD8+ T and NK cells in both tumor models and a decreased in PD-1 expression on immune effector cells. In summary, a combined approach consisting of activated NK cells and anti-PD-1 therapy is safe and results in a long-term tumor control which is accompanied by a massive tumor immune cell infiltration in 2 preclinical tumor models.
Highlights
Stress-inducible Heat shock protein 70 (Hsp70) is frequently overexpressed in the cytosol of many tumor entities where it fulfills a large variety of chaperoning functions such as folding/unfolding and transport of other proteins [1]
A combined regimen consisting of Hsp70-targeting activated NK cells and anti-Programmed death 1 (PD-1) inhibition was tested in a preclinical syngeneic glioblastoma and a xenograft lung cancer model
The mean fluorescence intensities of CD94, CD56 which serve as surrogate markers for the Hsp70-specificity increased significantly on CD3-negative NK cells compared to unstimulated control cells (Figure 1C)
Summary
Stress-inducible Hsp is frequently overexpressed in the cytosol of many tumor entities where it fulfills a large variety of chaperoning functions such as folding/unfolding and transport of other proteins [1]. Increased Hsp membrane densities are detectable in highly aggressive tumors including primary glioblastoma multiforme [2] and advanced non-small cell lung cancer (NSCLC) [6]. Both tumor types are debilitating, lifethreatening diseases with poor prognosis. A fully humanized IgG4 antibody, targets PD-1 and thereby attenuates inhibitory signals in immune cells such as T and NK cells [16, 18], which results in objective tumor responses predominantly in highly immunogenic (“hot”) tumors [19, 20] Despite these promising results a relevant proportion of patients, does not profit from immune checkpoint inhibitor blockade therapies. A combined regimen consisting of Hsp70-targeting activated NK cells and anti-PD-1 inhibition was tested in a preclinical syngeneic glioblastoma and a xenograft lung cancer model
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