Calreticulin promotes immunity and type I interferon-dependent survival in mice with acute myeloid leukemia

Abstract

Exposure of cancer cells to particular chemotherapeutic agents or γ-irradiation induces a form of cell death that stimulates an immune response in mice. This “immunogenic cell death” requires calreticulin (CRT) translocation to the plasma membrane, which has been shown to promote cancer cell phagocytosis. However, it remains unclear whether the effect of CRT on cancer cell phagocytosis is alone sufficient to affect tumor immunity. Acute myeloid leukemia (AML) cells expressing cell-surface CRT were generated in order to characterize the mechanism(s) through which CRT activates tumor immune responses. Potent immune-mediated control or rejection of AML was observed in mice with CRT-expressing leukemia. The “CRT effect” was ultimately T-cell dependent, but dendritic cells (DCs), and CD8α+ DCs in particular, were also necessary, indicating that CRT might act directly on these DCs. CRT-expressing AML cells were slightly more susceptible to phagocytosis by DCs in vivo, but this effect was unlikely to explain the potent immunity observed. CRT did not affect classical DC maturation markers, but induced expression of type I interferon (IFN), which was critical for its positive effect on survival. In conclusion, CRT functions as a “danger signal” that promotes a host type I IFN response associated with the induction of potent leukemia-specific T-cell immunity.

Diallyl disulfide down‐regulates calreticulin and promotes C/EBPα expression in differentiation of human leukaemia cells

“…Our previous studies demonstrated the down‐regulation of CRT during DADS‐induced differentiation in HL‐60 cells and indicated that CRT was involved in cell proliferation, invasion, and differentiation in DADS‐treated HL‐60 cells . Numerous studies have demonstrated that CRT could play an essential role in AML cell proliferation and invasion, and therefore may be an important target for AML .…”

Immunogenic stress and death of cancer cells: Contribution of antigenicity vs adjuvanticity to immunosurveillance

“…7 Moreover, stable transfection of cells with a CALR variant that is tethered to the surface of the plasma membrane is sufficient to preclude the growth of cancers in vivo. 7,65 To Figure 4B). Thus, the difference between parental vs hyperploid cells cultured in vitro in the expression of individual genes (black points in Figure 4C) is far more important than that between hyperploid cells passaged through ID vs IC mice (red points in Figure 4C).…”

“…Indeed, depletion of ERp57, which is required for CALR exposure, abolishes the immunoselection in favor of a reduced ploidy . Moreover, stable transfection of cells with a CALR variant that is tethered to the surface of the plasma membrane is sufficient to preclude the growth of cancers in vivo …”

Calreticulin arms NK cells against leukemia

“…While soluble DAMPs generally deliver chemotactic and immunostimulatory signals, CALR exposed on the membrane of dying cells and dead cell corpses supports their uptake by APCs in the context of type I IFN production. 4,5 Consistent with this notion, elevated levels of CALR on surface of malignant blasts has been linked with improved prognosis in patients with acute myeloid leukemia (AML), 6,7 correlating with superior T-cell dependent immunity. 6 As the contribution of lymphoid cells other than T cells to anticancer immunity driven by membrane-exposed CALR was unclear, we set to investigate the potential involvement of natural killer (NK) cells, which are gaining considerable momentum as actionable items for cancer immunotherapy.…”