Tumor-Associated Macrophages Produce PGE2 to Promote CD8+ T-cell Exhaustion and Drive Resistance to PD-L1 Blockade in Microsatellite-Stable Colorectal Cancer

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.