Serum cholesterol-riched apolipoprotein-B (apoB) containing lipoproteins predict the response to immune checkpoints inhibitors (ICIs) in non-small cell lung cancer (NSCLC) : A retrospective analysis
Authors: Hu Zixin , Zheng Yumin , Zheng Jiabin , Wang Yan , Liao Jiangquan , Lu Xingyu , Yu Yixuan , Liu Zhening , Li Jia , Dong Huijing , Cui Huijuan 
Published: June 2022

Abstract
Background
Lipid metabolism alternations reprogrammed tumor microenvironment (TME) to participate in clinical response to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). Body mass index (BMI), clinically used to assess body fat, has been positively correlated with ICIs monotherapy response. Circulating cholesterol is mainly packaged into apolipoproteins B (apoB) in the form of apoB containing lipoproteins, including low-density lipoprotein cholesterol (LDL-C) and remnant cholesterol (RC), which have been regarded as risk factors of tumorigenesis. The association between BMI, lipoproteins, and clinical outcome of ICIs is far from clear.
Methods
We performed a retrospective case-control analysis of 99 NSCLC patients treated with chemotherapy plus ICIs regimens in the department of oncology and lung cancer center of China-Japan Friendship Hospital between January 2019 to December 2021 and assessed the prognostic value of the BMI, serum lipids, lipoproteins, and apolipoproteins. Efficacy was assessed by response evaluation criteria in solid tumors (RECIST) version 1.1 and evaluated by the ICIs response (durable clinical benefit [DCB] / non-durable benefit [NDB]), best response (active/ non-active) and progression-free survival (PFS). The validation test and the mechanism exploration were performed with public data using bioinformatic methods.
Results
The contrary results to the ICIs single agents were obtained. BMI ≥ 25 kg/m2 was a risk indicator for NDB, non-active response to ICIs, shorter PFS with the confounders adjusted (OR = 6.06, 95% CI 2.05–19.89, p.val = 0.002; OR = 4.37, 95% CI 1.64–12.43, p.val = 0.004; HR = 3.08, 95% CI 1.63–5.82, p.val < 0.001). High cholesterol-riched apoB containing lipoproteins were risk factors for poor ICIs response. Low RC predicted the better ICIs response and the best response with the satisfied discriminative ability and the well-fitting calibration curves (OR = 0.12, 95%CI 0.02–0.63, p.val = 0.017; OR = 0.22. 95%CI 0.05–0.96, p.val = 0.047). Serum LDL-C predicted the longer PFS of ICIs with the added value to the BMI containing model (HR = 0.43, 95%CI 0.22–0.86, p.val = 0.016). Bioinformatic exploration in the TCGA-LUAD cohort showed that the APOB high group was infiltrated by elevated fibroblasts and other immune-suppressive cells to acquire the stromal barrier and form non-inflamed TME. Functional enrichment analysis indicated that the acquired ICIs resistance might be through the LRP6/5-Wnt-TGF-β axis which required laboratory experiments to verify.
Conclusions
In the NSCLC population treated with the combination of chemotherapy and ICIs, BMI ≥ 25 kg/m2, the elevated cholesterol-riched apoB containing lipoproteins are promise indicators for the poor ICIs response. Further large-scale validations and experimental explorations are needed.