Spatially resolved multimarker evaluation of CD274 (PD-L1)/PDCD1 (PD-1) immune checkpoint expression and macrophage polarisation in colorectal cancer

BackgroundThe CD274 (PD-L1)/PDCD1 (PD-1) immune checkpoint interaction may promote cancer progression, but the expression patterns and prognostic significance of PD-L1 and PD-1 in the colorectal cancer microenvironment are inadequately characterised.MethodsWe used a custom 9-plex immunohistochemistry assay to quantify the expression patterns of PD-L1 and PD-1 in macrophages, T cells, and tumour cells in 910 colorectal cancer patients. We evaluated cancer-specific mortality according to immune cell subset densities using multivariable Cox regression models.ResultsCompared to PD-L1(-) macrophages, PD-L1(+) macrophages were more likely M1-polarised than M2-polarised and located closer to tumour cells. PD-L1(+) macrophage density in the invasive margin associated with longer cancer-specific survival [P-trend = 0.0004, HR for the highest vs. lowest quartile, 0.52; 95% CI: 0.34-0.78]. T cell densities associated with longer cancer-specific survival regardless of PD-1 expression (P-trend < 0.005 for both PD-1(+) and PD-1(-) subsets). Higher densities of PD-1(+) T cell/PD-L1(+) macrophage clusters associated with longer cancer-specific survival (P-trend < 0.005).ConclusionsPD-L1(+) macrophages show distinct polarisation profiles (more M1-like), spatial features (greater co-localisation with tumour cells and PD-1(+) T cells), and associations with favourable clinical outcome. Our comprehensive multimarker assessment could enhance the understanding of immune checkpoints in the tumour microenvironment and promote the development of improved immunotherapies.

Automated summary

The expression patterns and prognostic significance of PD-L1 and PD-1 in the colorectal cancer microenvironment are inadequately characterised. This study found that PD-L1(+) macrophages and PD-1(+) T cells were associated with better clinical outcomes in colorectal cancer patients. These findings enhance the understanding of immune checkpoints in the tumor microenvironment and could contribute to the development of improved immunotherapies.