Myeloid derived suppressive cell expansion promotes melanoma growth and severity of autoimmunity by inhibiting CD40/IL-27 regulation in macrophages

Cancer Res. 2021 Oct 12:canres.1148.2021. doi: 10.1158/0008-5472.CAN-21-1148. Online ahead of print.ABSTRACTThe relationship between cancer and autoimmunity is complex. However, the incidence of solid tumors such as melanoma has increased significantly among patients with previous or newly diagnosed systemic autoimmune disease (AID). At the same time, immune checkpoint blockade (ICB) therapy of cancer induces de novo autoinflammation and exacerbates underlying AID, even without evident anti-tumor responses. Recently, systemic lupus erythematosus (SLE) activity was found to drive myeloid-derived suppressor cell (MDSC) formation in patients, a known barrier to healthy immune surveillance and successful cancer immunotherapy. Crosstalk between MDSCs and macrophages generally drives immune suppressive activity in the tumor microenvironment. However, it remains unclear how peripheral pre-generated MDSC under chronic inflammatory conditions modulates global macrophage immune functions and the impact it could have on existing tumors and underlying lupus nephritis. Here we show that pathogenic expansion of SLE-generated MDSCs by melanoma drives global macrophage polarization and simultaneously impacts the severity of lupus nephritis and tumor progression in SLE-prone mice. Molecular and functional data showed that MDSCs interact with autoimmune macrophages and inhibit cell surface expression of CD40 and the production of IL-27. Moreover, low CD40/IL-27 signaling in tumors correlated w...
Source: Cell Research - Category: Cytology Authors: Source Type: research