title: Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47.
abstract: 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.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford Cancer Center, and Ludwig Center at Stanford, Stanford, CA 94305, USA. mpchao@stanford.edu
authors.forename: Mark P
authors.initials: MP
authors.lastname: Chao
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Jaiswal
authors.forename: Rachel
authors.initials: R
authors.lastname: Weissman-Tsukamoto
authors.forename: Ash A
authors.initials: AA
authors.lastname: Alizadeh
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gentles
authors.forename: Jens
authors.initials: J
authors.lastname: Volkmer
authors.forename: Kipp
authors.initials: K
authors.lastname: Weiskopf
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Willingham
authors.forename: Tal
authors.initials: T
authors.lastname: Raveh
authors.forename: Christopher Y
authors.initials: CY
authors.lastname: Park
authors.forename: Ravindra
authors.initials: R
authors.lastname: Majeti
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
mesh_terms: D000818:Animals; D051928:CD47 Antigen / Q000378:metabolism*; D037282:Calreticulin / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism; D051379:Mice; D010587:Phagocytosis / Q000502:physiology*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism
chemical_list: D051928:CD47 Antigen; D037282:Calreticulin