Increased exposure of
calreticulin (CALR) on malignant cells is associated with
therapy-relevant adaptive immune responses and superior therapeutic outcome in solid
tumors and haemato-oncological diseases, because surface-exposed CALR acts as an 'eat-me' signal facilitating the phagocytosis of stressed and dying
cancer cells by immature dendritic cells, thus favoring antitumor immune responses. On the contrary, mutations of the CALR gene that cause the omission of the C-terminal KDEL endoplasmic reticulum retention motif from CALR
protein, resulting in its secretion from cells, act as oncogenic drivers in myeloproliferative
neoplasms via the autocrine activation of the
thrombopoietin receptor. We recently showed that soluble CALR inhibited the phagocytosis of
cancer cells by dendritic cells, thus dampening anticancer immune responses. Furthermore, systemic elevations of soluble CALR that is secreted from
tumors or that is artificially supplied by injection of the
recombinant protein decreased the efficacy of
immunotherapy. Thus, depending on its location, CALR can have immunostimulatory or immunosuppressive functions.