Protumor Steering of Cancer Inflammation by p50 NF-κB Enhances Colorectal Cancer Progression

Abstract

Although tumor-associated macrophages (TAM) display a M2-skewed tumor-promoting phenotype in most cancers, in colorectal cancer, both TAM polarization and its impact remain controversial. We investigated the role of the M2-polarizing p50 NF-κB subunit in orchestrating TAM phenotype, tumor microenvironment composition, and colorectal cancer progression. We first demonstrated, by parallel studies in colitis-associated cancer (CAC) and in genetically driven Apc^Min mouse models, that the p50-dependent inhibition of M1-polarized gut inflammation supported colorectal cancer development. In accordance with these studies, p50^-/- mice displayed exacerbated CAC with fewer and smaller tumors, along with enhanced levels of M1/Th1 cytokines/chemokines, including IL12 and CXCL10, whose administration restrained CAC development <i>in vivo</i> The inflammatory profile supporting tumor resistance in colons from p50^-/- tumor bearers correlated inversely with TAM load and positively with both recruitment of NK, NKT, CD8⁺ T cells and number of apoptotic tumor cells. In agreement, myeloid-specific ablation of p50 promoted tumor resistance in mice, whereas in colorectal cancer patients, a high number of p50⁺ TAMs at the invasive margin was associated with decreased <i>IL12A</i> and <i>TBX21</i> expression and worse postsurgical outcome. Our findings point to p50 involvement in colorectal cancer development, through its engagement in the protumor activation of macrophages, and identify a candidate for prognostic and target therapeutic intervention. <i>Cancer Immunol Res; 6(5); 578-93. ©2018 AACR</i>.