| Summary: | While immune checkpoint (IC) therapies, particularly those targeting the PD-1/PD-L1 axis, have revolutionized the treatment of melanoma and several other cancers, their effect remains very limited in colorectal cancer (CRC). To define a comprehensive landscape of ICs in the human CRC tumor microenvironment (TME), we evaluated, using multiparametric flow cytometry, their ex vivo expression via tumor-infiltrating lymphocytes (TILs) (n = 40 CRCs) as well as that of their respective ligands on tumor and myeloid cells (n = 29). Supervised flow cytometry analyses showed that (i) most CD3<sup>+</sup> TILs expressed PD-1 and TIGIT and, to a lesser extent, Tim-3, Lag3 and NKG2A, and (ii) EpCAM<sup>+</sup> tumor cells and CD11b<sup>+</sup> myeloid cells differed in their IC ligand expression profile, with a strikingly high expression of CD155 by tumor cells. An in situ analysis of IC and their ligands using immunohistochemistry on paraffin sections of CRC confirmed the overexpression of TIGIT and its ligand, CD155, in the TME. Most interestingly, an unsupervised clustering analysis of IC co-expression on CD4<sup>+</sup> and CD8<sup>+</sup> TILs identified two tumor subgroups, named IC<sup>high</sup> and IC<sup>low</sup>. Altogether, our findings highlight the TIGIT/CD155 axis as a potential target that could be used in combination IC therapy in CRC.
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