The tumor microenvironment in colorectal cancer therapy

© 2019 by the authors.The current standard-of-care for metastatic colorectal cancer (mCRC) includes chemotherapy and anti-angiogenic or anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, even though the addition of anti-angiogenic agents to backbone chemotherapy provides little benefit for overall survival. Since the approval of anti-angiogenic monoclonal antibodies bevacizumab and aflibercept, for the management of mCRC over a decade ago, extensive efforts have been devoted to discovering predictive factors of the anti-angiogenic response, unsuccessfully. Recent evidence has suggested a potential correlation between angiogenesis and immune phenotypes associated with colorectal cancer. Here, we review evidence of interactions between tumor angiogenesis, the immune microenvironment, and metabolic reprogramming. More specifically, we will highlight such interactions as inferred from our novel immune-metabolic (IM) signature, which groups mCRC into three distinct clusters, namely inflamed-stromal-dependent (IM Cluster 1), inflamed-non stromal-dependent (IM Cluster 2), and non-inflamed or cold (IM Cluster 3), and discuss the merits of the IM classification as a guide to new immune-metabolic combinatorial therapeutic strategies in mCRC.This work was funded by MINECO European Commission FEDER funds, “Una manera de hacer Europa” (SAF2015-66984-C2-1-R), Instituto de Salud Carlos III and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD CB17/04/00023), to T.M.T, and by Instituto de Salud Carlos III (PI13/01728 and PI19/00740) and Agencia de Gestió de Ajuts de Recerca (AGAUR) 2017 SGR 1174, to J.M.Peer reviewe