Targeting PD-L1 and TIGIT could restore intratumoral CD8 T cell function in human colorectal cancer.
Fiche publication
Date publication
mars 2022
Journal
Cancer immunology, immunotherapy : CII
Auteurs
Membres identifiés du Cancéropôle Est :
Pr GHIRINGHELLI François, Mme TRUNTZER Caroline, Dr LIMAGNE Emeric, Dr THIBAUDIN Marion
Tous les auteurs :
Thibaudin M, Limagne E, Hampe L, Ballot E, Truntzer C, Ghiringhelli F
Lien Pubmed
Résumé
Microsatellite stable colorectal cancers (MSS-CRC) are resistant to anti-PD-1/PD-L1 therapy but the combination of immune checkpoints inhibitors (ICI) could be a clue to reverse resistance. Our aim was to evaluate ex vivo the capacity of the combination of atezolizumab (anti-PD-L1) and tiragolumab (anti-TIGIT) to reactivate the immune response of tumor infiltrating lymphocytes (TILs) in MSS-CRC. We analysed CRC tumor tissue and the associated blood sample in parallel. For each patient sample, extensive immunomonitoring and cytokine production were tested. We generated an ex vivo assay to study immune reactivity following immune stimulation with checkpoint inhibitors of tumor cell suspensions. Three microsatellite instable (MSI) and 13 MSS-CRC tumors were analysed. To generalize our observations, bioinformatics analyses were performed on public data of single cell RNA sequencing of CRC TILs and RNA sequencing data of TCGA. Atezolizumab alone could only reactivate T cells from MSI tumors. Atezolizumab and tiragolumab reactivated T cells in 46% of MSS-CRC samples. Reactivation by ICK was observed in patients with higher baseline frequency of Th1 and Tc1 cells, and was also associated with higher baseline T cell polyfunctionality and higher CD96 expression. We showed that a high frequency of CD96 expression on T cells could be a surrogate marker of atezolizumab and tiragolumab efficacy. Together these data suggest that the association of atezolizumab and tiragolumab could restore function of CD4 and CD8 TILs in MSS-CRC and could be tested in a clinical trial in colorectal cancer patients with MSS status.
Mots clés
Anti-PDL1, Anti-TIGIT, CD8 T cells, Colorectal cancer, TNFα
Référence
Cancer Immunol Immunother. 2022 Mar 16;: