Plasma proteome and metabolites profiling reveals dynamics for adverse events and responses after neoadjuvant radiochemotherapy plus PDL1 blockade in microsatellite-stable locally advanced rectal cancer: A prospective longitudinal study

Neoadjuvant radio-chemotherapy (nCRT) plus immune checkpoint inhibitors (ICIs) have emerged as an effective antitumor regimen for locally advanced rectal cancer. Yet, few effective biomarkers are developed to monitor the therapy response. Herein, we investigate the longitudinal plasma proteome and metabolites profiling including 117 longitudinal samples from 50 patients who received nCRT plus PDL1 blockade therapy. Notably, the cholesterol metabolism is activated in the disease non-response group during the therapy. Correspondingly, the 1,4-cholestadienone, 7-methyloctanoylcarnitine and 3-hydroxybutyrylcarnitine, ABCA13, RAB3IP, GBA2 show significantly positive association with the cholesterol metabolism. Furthermore, by integrating proteome and metabolites approach, we identify a candidate metabolite (phosphatidylcholine, cholest-5-en-23-yn-3beta-ol) and proteome (APBB1IP, OLFM4, DNAJC19) that can reflect nCRT plus PDL1 response. Above, we establish a machine learning model to predict response, and the model performance is validated by repeated group-to-group validation with accuracy is 0.954. Thus, the plasma proteome and metabolites profiling strategy evaluate the alteration of cholesterol metabolism and identifies a panel of biomarkers.