Bortolomeazzi M, Keddar MR, Montorsi L, et al. - By performing an integrated analysis of the cancer tissue and related tumor microenvironment from patients managed with pembrolizumab (KEYNOTE 177 clinical trial) or nivolumab, researchers here intended to dissect the cellular as well as the molecular determinants of response to anti- programmed cell death 1 (PD1) immunotherapy in colorectal cancer (CRC). Response to anti-PD1 immunotherapy, in hypermutated CRCs, was not related to tumor mutational burden (TMB) but was linked with high clonality of immunogenic mutations, clonally expanded T cells, low activation of Wnt signaling, deregulation of the interferon gamma pathway, and active immune escape mechanisms. Findings clarified TMB’s limits as a predictor of response to anti-PD1 immunotherapy in CRC. It revealed a populace of antigen-presenting macrophages interacting with CD8 T cells that consistently segregate with response. Thus, it was inferred that the PD1-PDL1 (programmed death-ligand 1) interaction between CD8 T cells and macrophages is released by anti-PD1 agents to promote cytotoxic antitumor activity.