Abstract
Tumor specific cell surface localization and release of the stress inducible heat shock protein 70 (Hsp70) stimulate the immune system against cancer cells. A key immune stimulatory function of tumor-derived Hsp70 has been exemplified with the murine melanoma cell model, B16 overexpressing exogenous Hsp70. Despite the therapeutic potential mechanism of Hsp70 transport to the surface and release remained poorly understood. We investigated principles of Hsp70 trafficking in B16 melanoma cells with low and high level of Hsp70. In cells with low level of Hsp70 apparent trafficking of Hsp70 was mediated by endosomes. Excess Hsp70 triggered a series of changes such as a switch of Hsp70 trafficking from endosomes to lysosomes and a concomitant accumulation of Hsp70 in lysosomes. Moreover, lysosomal rerouting resulted in an elevated concentration of surface Hsp70 and enabled active release of Hsp70. In fact, hyperthermia, a clinically applicable approach triggered immediate active lysosomal release of soluble Hsp70 from cells with excess Hsp70. Furthermore, excess Hsp70 enabled targeting of internalized surface Hsp70 to lysosomes, allowing in turn heat-induced secretion of surface Hsp70. Altogether, we show that excess Hsp70 expressed in B16 melanoma cells diverts Hsp70 trafficking from endosomes to lysosomes, thereby supporting its surface localization and lysosomal release. Controlled excess-induced lysosomal rerouting and secretion of Hsp70 is proposed as a promising tool to stimulate anti-tumor immunity targeting melanoma.
Highlights
As tumors are often resistant to conventional therapies, development of alternative approaches is needed
We show that excess heat shock protein 70 (Hsp70) expressed in B16 melanoma cells diverts Hsp70 trafficking from endosomes to lysosomes, thereby supporting its surface localization and lysosomal release
Intracellular excess of Hsp70 alters its cell surface appearance - Excess Hsp70 was achieved in B16 murine melanoma cells with a tetracycline-inducible system
Summary
As tumors are often resistant to conventional therapies, development of alternative approaches is needed. An emerging and promising clinical approach is immunotherapy, where the patient’s immune system is primed to fight cancer. The stress inducible heat shock protein 70 (Hsp70) has been evaluated as a special tool for immunotherapy as it was shown to play a role in anti-tumor immunity mediated by both innate and adaptive immune system [1,2,3,4]. Stress inducible Hsp is normally confined to the cytoplasm and exerts cytoprotective, anti-apoptotic functions [5, 6]. Extracellular Hsp exerts a dual, “chaperokine” function acting as a chaperone and a cytokine. Released Hsp, due to its chaperone function, has the capacity to present tumor antigens for the adaptive immune system. Extracellular Hsp, even in the absence of immunogenic peptides, has been considered as a potent danger signal for the immune system [3, 18]
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