Protumor steering of cancer inflammation by p50 nf-kb enhances colorectal cancer progression

Chiara Porta, Alessandro Ippolito, Francesca Maria Consonni, Lorenzo Carraro, Giuseppe Celesti, Carmen Correale, Fabio Grizzi, Fabio Pasqualini, Silvia Tartari, Maurizio Rinaldi, Paolo Bianchi, Fiorella Balzac, Stefania Vetrano, Emilia Turco, Emilio Hirsch, Luigi Laghi, Antonio Sica

Research output: Contribution to journalArticlepeer-review

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-kB 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 ApcMin 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 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, CD8þ 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 p50þ TAMs at the invasive margin was associated with decreased IL12A and TBX21 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.

Original languageEnglish
Pages (from-to)578-593
Number of pages16
JournalCancer immunology research
Volume6
Issue number5
DOIs
Publication statusPublished - May 1 2018

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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