Data from Myeloid-Derived Suppressive Cell Expansion Promotes Melanoma Growth and Autoimmunity by Inhibiting CD40/IL27 Regulation in Macrophages

• DOI: 10.1158/0008-5472.c.6513930.v1
• Publication Date: 2023-03-31T21:17:36Z
• Authors: Julio C. Valencia; Rebecca A. Erwin-...; Paul E. Clavijo; Clint Allen; Michael E. Sanford; Chi-Ping Day; Megan M. Hess; Morgan Johnson; Jie Yin; John M. Fenimore; Ian A. Bettencourt; Koichi Tsuneyama; Maria E. Romero; Kimberly D. Klarmann; Peng Jiang; Heekyong R. Bae; Daniel W. McVicar; Glenn Merlino; Elijah F. Edmondson; Niroshana Anandas...; Howard A. Young
• Keywords: Macrophage polarization; Cancer Immunotherapy; Immune checkpoint

<div>Abstract<p>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 same time, immune checkpoint blockade (ICB) therapy induces <i>de novo</i> autoinflammation exacerbates underlying AID, even without evident antitumor responses. Recently, lupus erythematosus (SLE) activity was found to drive myeloid-derived suppressor cell (MDSC) formation in patients, a known barrier healthy surveillance successful immunotherapy. Cross-talk MDSCs macrophages generally drives suppressive tumor microenvironment. it remains unclear how peripheral pregenerated MDSC under chronic inflammatory conditions modulates global macrophage functions impact could have on existing nephritis. Here we show that pathogenic expansion SLE-generated by polarization simultaneously impacts severity nephritis progression SLE-prone mice. Molecular functional data showed interact inhibit surface expression CD40 production IL27. Moreover, low CD40/IL27 signaling correlated high tumor-associated infiltration ICB resistance both murine human exhibiting active IFNγ signatures. These results suggest preventing reprogramming induced MDSC-mediated inhibition provides precision immunotherapy strategy, supporting an original advantageous approach treat within established landscapes.</p>Significance:<p>Myeloid-derived cells induce suppressing progression, affecting facilitating preexisting landscapes.</p></div>