Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47
By M. Chao, Siddhartha Jaiswal, R. Weissman-Tsukamoto, Ash A. Alizadeh, Andrew J. Gentles, J. Volkmer, K. Weiskopf, S. Willingham, T. Raveh, Christopher Y. Park and 2 more. Science Translational Medicine, 2010
737 citations recorded by the source corpus.
Calreticulin-induced phagocytosis of cancer cells can be counterbalanced by CD47 expression. Eat Up! Immune cells constantly patrol the body on a search and destroy campaign against foreign invaders. Designed to detect differential molecular signals, cells of the immune system can distinguish healthy from infected tissue by the types of proteins produced: Infected cells, for example, often produce unfamiliar proteins, which then activate innate immune cells to “eat” (phagocytose) the infected ones. Cancer cells also carry aberrant cargo such as unfamiliar proteins or normal proteins at abnormal levels, yet these cells frequently escape immune attack because they express a “don’t eat me” signal, the cell surface protein CD47. Blocking this signal on a cancer cell makes them targets for phagocytosis, but surprisingly does not do the same for normal cells that express CD47. Chao et al. have now identified calreticulin as the “eat me” signal on cancer cells that leads to phagocytosis when the counterbalancing “don’t eat me” signal CD47 is blocked. Calreticulin is a pro-phagocytic molecule that is highly expressed on the surface of several types of human cancer cells, including acute myeloid and lymphoblastic leukemias, chronic myeloid leukemia, non-Hodgkin’s lymphoma, bladder cancer, glioblastoma, and ovarian cancer. However, calreticulin is expressed only at very low levels on normal cells. Chao et al. found a correlation between calreticulin and CD47 expression levels on cancer cells and showed that blocking the interaction between calreticulin and its ligand prevented phagocytosis initiated by blocking the “don’t eat me” signal CD47. Moreover, high calreticulin expression on cancer cells was a poor prognostic indicator in human patients with neuroblastoma, bladder cancer, and non-Hodgkin’s lymphoma. Therefore, a balance between calreticulin and CD47 expression in cancer cells may be a double-edged sword: In the absence of a CD47 blocker, this equilibrium may support tumor cell survival, but when CD47 function is inhibited, the presence of calreticulin tells immune cells to “eat up!” This information provides a key insight for the therapeutic development of CD47-inhibitory agents. Under normal physiological conditions, cellular homeostasis is partly regulated by a balance of pro- and anti-phagocytic signals. CD47, which prevents cancer cell phagocytosis by the innate immune system, is highly expressed on several human cancers including acute myeloid leukemia, non-Hodgkin’s lymphoma, and bladder cancer. Blocking CD47 with a monoclonal antibody results in phagocytosis of cancer cells and leads to in vivo tumor elimination, yet normal cells remain mostly unaffected. Thus, we postulated that cancer cells must also display a potent pro-phagocytic signal. Here, we identified calreticulin as a pro-phagocytic signal that was highly expressed on the surface of several human cancers, but was minimally expressed on most normal cells. Increased CD47 expression correlated with high amounts of calreticulin on cancer cells and was necessary for protection from calreticulin-mediated phagocytosis. Blocking the interaction of target cell calreticulin with its receptor, low-density lipoprotein receptor–related protein, on phagocytic cells prevented anti-CD47 antibody–mediated phagocytosis. Furthermore, increased calreticulin expression was an adverse prognostic factor in diverse tumors including neuroblastoma, bladder cancer, and non-Hodgkin’s lymphoma. These findings identify calreticulin as the dominant pro-phagocytic signal on several human cancers, provide an explanation for the selective targeting of tumor cells by anti-CD47 antibody, and highlight the balance between pro- and anti-phagocytic signals in the immune evasion of cancer.
Subfields: Cell Biology, Immunology
View Paper: https://www.semanticscholar.org/paper/2a3f42727e87c02f3f21fa583a6ddc2b943497e9
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Citations in the corpus
- Consensus guidelines for the detection of immunogenic cell death (2014, background): “Interestingly, the phagocytosis-stimulatory effects of CALR is robustly counterbalanced by CD47, which is highly expressed by a large panel of solid and hematopoietic tumors.(166) This latter observation suggests that various neoplasms benefit from avoiding the effects of CALR exposure, perhaps as t”
- A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death (2012, neutral): “Finally, immunogenic apoptosis is sometimes associated with disappearance of certain surface-associated molecules, for example CD47, which are referred to as ‘do not eat me’ signals (Chao et al , 2010).”
- The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors (2012, background): “Cell surface calreticulin is present on a subset of cells in all human leukemias, lymphomas, and solid cancers, but not on nontumor cells (37).”