Fiche publication
Date publication
novembre 2025
Journal
Cancer research
Auteurs
Membres identifiés du Cancéropôle Est :
Pr GHIRINGHELLI François
,
Mme TRUNTZER Caroline
,
Dr LIMAGNE Emeric
,
Dr DERANGERE Valentin
,
Dr FUMET Jean-David
,
Dr THIBAUDIN Marion
Tous les auteurs :
Fumet JD, Latour C, Nuttin L, Derangère V, Ilie A, Russo P, Hampe L, Daumoine S, Thibaudin M, Truntzer C, Ghiringhelli F, Limagne E
Lien Pubmed
Résumé
Immune checkpoint blockade treatment is highly effective in microsatellite instable (MSI) colorectal cancer (CRC). However, microsatellite stable (MSS) tumors, are intrinsically resistant to immunotherapy. Here, we sought to better understand the mechanisms of resistance to anti-PD-L1 therapy in CRC by characterizing the immune profiles of MSS and MSI tumor models. While both tumor types presented intratumoral CD8+ T cell and PD-L1 expression, the exhausted CD8+ T cell phenotypes differed. In the MSS tumors, exhausted CD8+ T cells co-expressed PD-1 and TIGIT and exhibited a terminal exhausted profile with low cytokine secretion and limited cytotoxic function. In contrast, PD-1+ CD8+ T cells in MSI tumors did not express TIGIT and displayed higher cytokine and cytotoxic activities. Interestingly, immunosuppressive M2-like tumor-associated macrophages (TAM) accumulated in MSI tumors and positively correlated with PD-1+ TIGIT+ CD8+ T cell frequency. M2-like TAM depletion reduced TIGIT expression, increased CD8+ T cell function, and improved efficacy of PD-L1 blockade. Transcriptomic analysis revealed elevated COX1/2 expression in TAMs in MSS tumors compared to MSI tumors. COX2 and prostaglandin E2 receptor inhibition impeded TIGIT expression and restored CD8+ T cell activity, while PGE2 triggered TIGIT upregulation in CD8+ T cells. Single-cell, spatial, and bulk transcriptomic data from CRC patients substantiated the correlation between elevated TIGIT in CD8+ T cell and COX1/2 in TAMs. Together, these data uncover the role of the TAM axis in inhibiting PD-L1 efficacy in MSS CRC and support the utility of combining anti-PD-L1 therapy with TIGIT blockade, PGE2 treatment, or M2-like TAM inhibition in CRC.
Référence
Cancer Res. 2025 11 6;:
