Dynamic changes in peripheral blood monocytes early after anti-PD-1 therapy predict clinical outcomes in...

Immune checkpoint inhibitors are effective for advanced hepatocellular carcinoma (HCC), but there remains a need for peripheral blood biomarkers to predict the clinical response. Here, we analyzed the peripheral blood of 45 patients with advanced HCC who underwent nivolumab. During treatment, frequency of classical monocytes (CD14⁺CD16^-) was increased on day 7, and the fold increase in the frequency on day 7 over day 0 (cMonocyte_D7/D0) was significantly higher in patients with durable clinical benefit (DCB) than in patients with non-DCB (NDB). When we analyzed transcriptomes of classical monocytes, CD274, gene encoding PD-L1, was upregulated in NDB patients compared to DCB patients at day 7. Notably, gene signature of suppressive tumor-associated macrophages, or IL4l1⁺PD-L1⁺IDO1⁺ macrophages, was enriched after treatment in NDB patients, but not in DCB patients. Accordingly, the fold increase in the frequency of PD-L1⁺ classical monocytes at day 7 over day 0 (cMonocyte-PDL1_D7/D0) was higher in NDB patients than DCB patients. The combined biomarker cMonocyte_D7/D0/cMonocyte-PDL1_D7/D0 was termed the "monocyte index", which was significantly higher in DCB patients than NDB patients. Moreover, the monocyte index was an independent prognostic factor for survival. Overall, our results suggest that early changes of circulating classical monocytes, represented as a monocyte index, could predict clinical outcomes of advanced HCC patients undergoing anti-PD-1 therapy.