Pro-tumor steering of cancer inflammation by p50 NF-κB enhances colorectal cancer progression

Although tumor-associated macrophages (TAMs) display a M2-skewed tumor-promoting phenotype in most cancers, in colorectal cancer (CRC), 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 CRC progression. We first demonstrate, by parallel studies in colitis-associated cancer (CAC) and in genetically driven ApcMin mouse models, that the p50-dependent inhibition of M1-polarized gut inflammation supports CRC development. In accordance with these studies, p50-/- mice displayed exacerbated colitis associated with fewer and smaller tumors, along with enhanced levels of M1/Th1 cytokines/chemokines, including IL12 and CXCL10, whose administration restrained CAC development in vivo. 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 CRC patients, a high number of p50+ TAMs at the invasive margin was associated with decreased IL12A and TBX21 expression and worse post-surgical outcome. Our findings point to p50 involvement in CRC development, through its engagement in the pro-tumor activation of macrophages, and identify a new candidate for prognostic and target therapeutic intervention.