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

TitleMyeloid derived suppressive cell expansion promotes melanoma growth and severity of autoimmunity by inhibiting CD40/IL-27 regulation in macrophages.
Publication TypeJournal Article
Year of Publication2021
AuthorsValencia JC, Erwin-Cohen RA, Clavijo PE, Allen C, Sanford ME, Day C-P, Hess MM, Johnson M, Yin J, Fenimore JM, Bettencourt IA, Tsuneyama K, Romero ME, Klarmann KD, Jiang P, Bae HR, McVicar DW, Merlino G, Edmondson EF, Anandasabapathy N, Young HA
JournalCancer Res
Date Published2021 Oct 12
ISSN1538-7445
Abstract

The 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 with high TAM infiltration and ICB therapy resistance both in murine and human melanoma exhibiting active IFN╬│ signatures. These results suggest that preventing global macrophage reprogramming induced by MDSC-mediated inhibition of CD40/IL-27 signaling provides a precision melanoma immunotherapy strategy, supporting an original and advantageous approach to treat solid tumors within established autoimmune landscapes.

DOI10.1158/0008-5472.CAN-21-1148
Alternate JournalCancer Res
PubMed ID34642183