Tumor-Associated Macrophages Produce PGE2 to Promote CD8+ T-cell Exhaustion and Drive Resistance to PD-L1 Blockade in Microsatellite-Stable Colorectal Cancer
Jean-David Fumet, Charlène Latour, Lisa Nuttin, Valentin Dérangère, Alis Ilie, Pier Paolo Di Russo, Léa Hampe, Susy Daumoine, Marion Thibaudin, Caroline Truntzer, François Ghiringhelli, Emeric Limagne
Abstract
Immune checkpoint blockade treatment is highly effective in microsatellite-instable (MSI) colorectal cancer. However, microsatellite-stable (MSS) tumors, which represent 95% of metastatic colorectal cancer, are intrinsically resistant to immunotherapy. In this study, we sought to better understand the mechanisms of resistance to anti-PD-L1 therapy in colorectal cancer by characterizing the immune profiles of MSS and MSI tumor models. Although both tumor types presented intratumoral CD8+ T-cell responses and PD-L1 expression, the exhausted CD8+ T-cell phenotypes differed. In MSS tumors, exhausted CD8+ T cells coexpressed PD-1 and T-cell immunoglobulin and ITIM domain (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 with MSI tumors. COX2 and prostaglandin E2 (PGE2) receptor inhibition impeded TIGIT expression and restored CD8+ T-cell activity, whereas PGE2 triggered TIGIT upregulation in CD8+ T cells. Single-cell, spatial, and bulk transcriptomic data from patients with colorectal cancer 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 colorectal cancer and support the utility of combining anti-PD-L1 therapy with TIGIT blockade, PGE2 treatment, or M2-like TAM inhibition in colorectal cancer. SIGNIFICANCE: Targeting PGE2 signaling activated by tumor-associated macrophages sensitizes microsatellite-stable colon tumors to immune checkpoint blockade by limiting the emergence of an exhausted PD-1+ TIGIT+ CD8+ T population.