Heat Shock Proteins in Cancer Immunotherapy

Abstract

Heat shock proteins (HSPs) are highly conserved molecular chaperones with divergent roles in various cellular processes. The HSPs are classified according to their molecular size as HSP27, HSP40, HSP60, HSP70, and HSP90. The HSPs prevent nonspecific cellular aggregation of proteins by maintaining their native folding energetics. The disruption of this vital cellular process, driven by the aberrant expression of HSPs, is implicated in the progression of several different carcinomas. Many HSPs are also actively involved in promoting the proliferation and differentiation of tumor cells, contributing to their metastatic phenotype. Upregulation of these HSPs is associated with the poor outcome of anticancer therapy in clinical settings. On the other hand, these highly expressed HSPs may be exploited as viable immunotherapeutic targets for different types of cancers. This review discusses recent advances and perspectives on the research of HSP-based cancer immunotherapy.

Figure 1

Heat shock proteins in cancer. Cancer cells are exposed to several stress factors from the extracellular milieu of tumor microenvironment. These stress factors activate heat shock transcription factors (HSFs) by facilitating their dissociation from heat shock proteins and phosphorylating them. The heat shock transcription factors are then translocated into the nucleus where they bind with heat shock elements (HSE) and initiate the transcription of heat shock proteins like HSP27, HSP70, and HSP90. The HSPs are exported into the tumor microenvironment modulating the immune response against cancer cells. In immunosuppressive conditions, the HSPs enhance the survival and proliferation of cancer cells by activating their cellular protection machinery. The HSPs may also stimulate the anticancer immune response under optimal conditions, thereby maintaining a fine balance between cell death and survival.

Figure 2

Overview of pathways in tumor antigen cross-presentation by the HSPs to the APCs. Cancer cells display limited surface peptides or antigens which are released into the extracellular milieu. These antigens are recognized by HSPs through HSP-receptors, such as SRECI and LOX-1. The HSP peptide complex may be either engulfed into the DCs through CD91 receptor-mediated endocytosis or recognized by the cognate receptors on the surface of these DCs, resulting in their activation. This leads to a cascade of subsequent innate and adaptive immunological responses against cancer cells. The activated DCs activate the γδ T cells and NK T cells which may facilitate the lysis of the cancer cells. These DCs also produce inflammatory cytokines, chemokines, and nitric oxide. The activation of APCs results in the recognition and killing of cancer cells through cytotoxic CD8+ T-lymphocytes response. The lysis of cancer cells releases cancer antigens into the extracellular milieu leading to the formation of memory CD8+ T cells. The cross-presentation of HSP peptide complex to APCs is therefore an effective process bridging innate and adaptive immune response and mounting an optimal anticancer immunity. The inactive DCs/CD8+ T cells are represented in light color while the activated cells are represented in dark color. This illustration has been created with Biorender.com. DC-dendritic cells.