THE ROLE OF BLOOD CHOLESTEROL QUALITY IN PATIENTS WITH ADVANCED CANCER RECEIVING IMMUNE CHECKPOINT INHIBITORS

Introduction: Immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape of several solid tumors. However, a limited fraction of patients (pts) achieves a long-term benefit. Cholesterol, both at plasmatic and intracellular level, emerged as promising biomarker. Cholesterol efflux capacity (CEC) mediated by ABCA1 and ABCG1 and cholesterol passive diffusion (CPD) are critically implicated in modulating immune function through T cells activation. The aim of the present study was to investigate the CEC mediated by serum transporters (ABCA1- and ABCG1) and CPDwith the clinical outcome of advanced non-small cell lung cancer (NSCLC) and metastatic renal cell carcinoma (mRCC) pts treated with ICIs. Material and methods: We retrospectively enrolled advanced NSCLC and mRCC consecutively treated with ICIs at our center between October 2013 and October 2018, in order to correlate CEC and CPD with the overall survival (OS, primary endpoint). The secondary endpoints were the correlation between CEC and CPD with progression-free-survival (PFS) and clinical benefit (CB, complete/partial response or stable disease). Univariable and multivariable semi-parametric Cox regression models were implemented to assess associations between cholesterol parameters and survival; the logistic regression model was used to assess the association with the CB. Stepwise backword selection approach was performed to identify the most parsimonious model through Akaike information criterion (AIC). Results: Among 70 pts enrolled, a serum sample suitable for CEC and CPD determination was available for 68 pts. 94.2% of pts was affected by NSCLC. Median OS and median PFS was 5.2 and 2.4 months, respectively. Thirty-two pts (45.7%) obtained a CB as best response to ICIs. At the univariate analysis blood cholesterol, and serum ABCA1, ABCG1, CPD and CLC were associated with outcomes (OS, PFS, CB). At the multivariate analysis, only CPD was confirmed as protection factor for both OS and PFS as well as for CB [HR 0.77 (95%CI 0.67-0.89), p < 0.001; HR 0.81 (95%CI 0.74-0.90), p < 0.001; HR 1.26 (1.10-1.48) 95%CI, p < 0.003]. Conclusions: CEC and CPD, the major cholesterol diffusion modalities, may be considered as indirect measure of quality of total cholesterolemia. The positive association of CPD with both PFS and OS might reflect the presence of more immature HDL particles and more inflamed context that can explain the better response to ICI. Further prospective studies are needed.