Proteomic and metabolomic features in patients with HCC responding to lenvatinib and anti-PD1 therapy

Combination therapy (lenvatinib/programmed death-1 (PD1) inhibitor) is effective for treating unresectable hepatocellular carcinoma (uHCC). We reveal that responders have better overall and progression-free survival, as well as high tumor mutation burden and special somatic variants. We analyze the proteome and metabolome of 82 plasma samples from upatients with HCC (n=51) and normal controls (n=15), revealing that individual differences outweigh treatment differences. Responders have increased alternative/lectin complement pathway and lysophosphatidylcholines (LysoPCs), predicting better prognosis. Non-responders are enriched for immunoglobulins, predicting worse outcomes. Compared to normal controls, HCC plasma proteins show acute inflammatory response and platelet activation, while LysoPCs decrease. Combination therapy raises LysoPCs/PCs in responders. Logistic-regression/random-forest models using metabolomic features achieve good performance in prediction of responders. Proteomic analysis of cancer tissues unveils molecular features that are associated with the side effects in responders receiving combination therapy. In conclusion, our analysis identifies plasma features associated with uHCC responders to combination therapy.