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Abstract: Recent data suggest that vascular endothelial growth factor receptor inhibitor (VEGFRi) could enhance the anti-tumor activity of the anti-PD-1 antibody in colorectal cancer (CRC) with microsatellite stability (MSS). However, the comparison between this combination and standard third-line VEGFRi treatment is not established and reliable biomarkers are still lacking. We retrospectively enrolled MSS CRC patients receiving anti-PD-1 antibody plus VEGFRi (combination group, n=54) or VEGFRi alone (VEGFRi group, n=32), and their efficacy and safety were evaluated. We additionally examined the immune characteristics of the MSS CRC tumor microenvironment (TME) through single-cell and spatial transcriptomic data, and an MSS CRC immune cell-related signature (MCICRS) predicting the clinical outcomes of MSS CRC patients receiving immunotherapy was developed and validated in our in-house cohort. Compared to VEGFRi alone, anti-PD-1 antibody and VEGFRi combination exhibited a prolonged survival benefit (median progression-free survival: 4.4 vs. 2.0 months, P=0.0024; median overall survival: 10.2 vs. 5.2 months, P=0.0038) and similar adverse events incidence. Through single-cell and spatial transcriptomic analyses, we determined 10 MSS CRC-enriched immune cell types and their spatial distribution, including naïve CD4T, regulatory CD4T, Th17, exhausted CD8T, cytotoxic CD8T, proliferated CD8T, NK, plasma, and classical and intermediated monocytes. Based on a systemic meta-analysis and 10 machine learning algorithms, we obtained MCICRS, an independent risk factor for the prognosis of MSS CRC patients. Further analyses demonstrated that the low-MCICRS group presented a higher immune cell infiltration and immune-related pathway activation, and hence a significant relation with the superior efficacy of pan-cancer immunotherapy. More importantly, the predictive value of MCICRS in MSS CRC receiving immunotherapy was also validated with the in-house cohort. Anti-PD-1 antibody combined with VEGFRi presented an improved clinical benefit in MSS CRC with manageable toxicity. MCICRS could serve as a robust and promising tool with which to predict clinical outcomes for individual MSS CRC patients receiving immunotherapy.