Calreticulin—Multifunctional Chaperone in Immunogenic Cell Death: Potential Significance as a Prognostic Biomarker in Ovarian Cancer Patients

Abstract

Immunogenic cell death (ICD) is a type of death, which has the hallmarks of necroptosis and apoptosis, and is best characterized in malignant diseases. Chemotherapeutics, radiotherapy and photodynamic therapy induce intracellular stress response pathways in tumor cells, leading to a secretion of various factors belonging to a family of damage-associated molecular patterns molecules, capable of inducing the adaptive immune response. One of them is calreticulin (CRT), an endoplasmic reticulum-associated chaperone. Its presence on the surface of dying tumor cells serves as an “eat me” signal for antigen presenting cells (APC). Engulfment of tumor cells by APCs results in the presentation of tumor’s antigens to cytotoxic T-cells and production of cytokines/chemokines, which activate immune cells responsible for tumor cells killing. Thus, the development of ICD and the expression of CRT can help standard therapy to eradicate tumor cells. Here, we review the physiological functions of CRT and its involvement in the ICD appearance in malignant disease. Moreover, we also focus on the ability of various anti-cancer drugs to induce expression of surface CRT on ovarian cancer cells. The second aim of this work is to discuss and summarize the prognostic/predictive value of CRT in ovarian cancer patients.

The Role of Soluble Low-Density Lipoprotein Receptor-Related Protein-1 in Obstructive Sleep Apnoea

“…CALR is a marker of immunogenic cells death [16]. Although hypoxia induces its translocation to the cell surface and extracellular release [41], we did not find a significant relationship between CALR levels and markers of IH.…”

“…Calreticulin (CALR) is an endoplasmic reticulum-associated chaperone which is exposed to the cell surface and even released extracellularly upon various stress stimuli, such as inflammation and hypoxia [16]. On the cellular surface it binds with LRP-1 of the immune cells and participates in the immunogenic cell death.…”

Ultrasound (US)-activated redox dyshomeostasis therapy reinforced by immunogenic cell death (ICD) through a mitochondrial targeting liposomal nanosystem

“…Alternatively, CRT exposure on the cell membrane was further assessed by immunofluorescence labeling and detection by flow cytometry, and the results were consistent with the confocal microscopy findings ( Figure S11 ). Therapy-induced CRT translocation onto the plasma membrane can be attributed to activation of the stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) under imbalanced intracellular redox homeostasis, which leads to the phosphorylation of eukaryotic translation initiation factor (eIF2α) 61 . In another aspect, the release of HMGB1 is recognized as the late ICD event and can act as a cytokine that binds to APCs for optimal antigen presentation, leading to protective immunity 62 .…”

Immunogenic Cell Death Induction by Ionizing Radiation

“…CD91, also known as low-density lipoprotein receptor-related protein 1, is a endocytic and cell signaling receptor expressed on the surface of both normal and tumor cells ( 19 ). The CRT–CD91 interaction leads to the release of TNF-α (tumor necrosis factor-α) and IL-6 ( 20 ). CD91 also combines with HSP90 to facilitate cross-presentation ( 21 ).…”

“…Secreted from mature DCs, IL-6, IL-1β, TNF-α, and type γ interferon (IFN-γ) promote the differentiation of T cells into the CD8 + phenotype. Then, CD8 + T cells are activated by antigen cross-presentation from DCs to become cytotoxic T lymphocytes (CTLs) ( 20 ). Ultimately, CTLs induce tumor cell apoptosis through the release of perforin and granzyme B, or a combination of Fas ligand (FasL) with Fas ( Figure 1 ) ( 11 , 26 ).…”