Endoplasmic Reticulum Chaperones and Their Roles in the Immunogenicity of Cancer Vaccines

Abstract

The endoplasmic reticulum (ER) is a major site of passage for proteins en route to other organelles, to the cell surface, and to the extracellular space. It is also the transport route for peptides generated in the cytosol by the proteasome into the ER for loading onto major histocompatibility complex class I (MHC I) molecules for eventual antigen presentation at the cell surface. Chaperones within the ER are critical for many of these processes; however, outside the ER certain of those chaperones may play important and direct roles in immune responses. In some cases, particular ER chaperones have been utilized as vaccines against tumors or infectious disease pathogens when purified from tumor tissue or recombinantly generated and loaded with antigen. In other cases, the cell surface location of ER chaperones has implications for immune responses as well as possible tumor resistance. We have produced heat-shock protein/chaperone protein-based cancer vaccines called “chaperone-rich cell lysate” (CRCL) that are conglomerates of chaperones enriched from solid tumors by an isoelectric focusing technique. These preparations have been effective against numerous murine tumors, as well as in a canine with an advanced lung carcinoma treated with autologous CRCL. We also published extensive proteomic analyses of CRCL prepared from human surgically resected tumor samples. Of note, these preparations contained at least 10 ER chaperones and a number of other residents, along with many other chaperones/heat-shock proteins. Gene ontology and network analyses utilizing these proteins essentially recapitulate the antigen presentation pathways and interconnections. In conjunction with our current knowledge of cell surface/extracellular ER chaperones, these data collectively suggest that a systems-level view may provide insight into the potent immune stimulatory activities of CRCL with an emphasis on the roles of ER components in those processes.

Calnexin Impairs the Antitumor Immunity of CD4+ and CD8+ T Cells

“…Endoplasmic reticulum (ER) chaperones, including BiP/ GRP78, calreticulin, calnexin, GRP94, and ERP57, are a large family of proteins that have been discovered to have many important roles in maintaining ER homeostasis and contributing to cancer cell survival and progression. The correlation between ER chaperone expression and tumorigenesis has been extensively studied in various cancers, and most reports have indicated that these proteins promote the proliferation, migration, and attachment of cancer cells (9)(10)(11)(12)(13). The ER chaperone calnexin, which is an ER-specific type I transmembrane protein, regulates the folding and quality control of newly synthesized glycoproteins (14).…”

Endoplasmic Reticulum Chaperones at the Tumor Cell Surface and in the Extracellular Space

“…Chaperony ER se mohou díky lokalizaci do buněčné membrány nebo extracelulárního prostředí přímo podílet na modulaci imunitní odpovědi buněk [29]. Imunogenní vlastnosti extracelulárních chaperonů ER jsou spjaté s proteiny, které se na povrchu buňky chovají jako "signál označující nebezpečí" a jsou schopné interagovat s receptory buněk imunitního systému.…”

“…Kalnexin patří stejně jako kalretikulin mezi proteiny ER detekované na buněčné membráně. Funkcí povrlární chaperony, jako jsou HSP27, HSP60, HSP70, GRP94, HSP90 nebo GRP170, se mohou vázat s TLR (toll like receptor) receptory, které jsou obvykle exprimovány dendritickými buňkami a makrofágy, a tudíž se účastní vrozené imunitní odpovědi organizmu [29]. Jako chaperony ER schopné aktivovat imunitní systém na povrchu buňky nebo v extracelulár-ním prostředí byly popsány kalretikulin, GRP78 a GRP94 [30][31][32][33][34].…”

Editorial: Endoplasmic Reticulum and Its Role in Tumor Immunity

“…As an alternative to the stealth-like cancer eradication by TCR-transduced T cells, Graner and colleagues have proposed a more “blanket-bombing” approach. They describe the development of a vaccination rationale comprising of chaperone-rich cell lysates (CRCL) purified from solid tumors designed to induce a plethora of immune responses ( 30 ).…”