Heat Shock Proteins, Autoimmunity, and Cancer Treatment

Figure 1

The cell biology of the tumor milieu: the role of heat shock proteins. The upper part of the figure depicts tumor cells (pale blue), including cancer cells with a cuboid epithelial shape and more spindle-shaped cancer stem cells (CSCs), suggesting the EMT (epithelial-mesenchymal transition) characteristics ascribed to CSC. The tumor is represented as a heterogeneous cell colony containing myeloid suppressor cells (MDSCs; green), Treg (dark blue), and tumor-associated fibroblast (TAF; orange). Dominant cytokines in the tumor microenvironment include IL-10 and TGF𝛽. The growth factors FGF and VEGF are secreted by TAF. To the left of the figure is depicted a tumor capillary containing CD4+ T cells (red) that have stalled at the capillary wall. Tumor cells are depicted as secreting Hsp70-containing exosomes (black circles) that recruit MDSCs as well as free Hsp70 that may also trigger immunosuppressive responses. The lower section suggests the potential effects of therapy using molecular chaperone vaccines, in which IL-6 is now at high levels and the cytokine profile is proinflammatory, cognate CTL has crossed the capillary wall, penetrated the tumor interstitial spaces, and recognized MHC class I associated with tumor antigens. Such tumor cells can then be killed in an antigen-specific manner. In addition, Hsp70-peptide complexes (Hsp70.PC) are secreted from necrotic tumor cells and can trigger anticancer CTL after entering APC and cross-presentation to CD4+ T cells in afferent lymph nodes.