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

Abstract

Objectives: Lipid metabolism alternations reprogrammed tumor microenvironment (TME) to influence the response to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). Body mass index (BMI) and apolipoproteins B (apoB) including low-density lipoprotein cholesterol (LDL-C) and remnant cholesterol (RC) reflect the lipid metabolism status. The associations between BMI, lipoproteins, and clinical outcome of ICIs are far from clear. Methods: 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 was performed. The prognostic value of the BMI, serum lipids, lipoproteins, and apolipoproteins were assessed. Efficacy was 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: 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 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 showed that the LUAD samples with high APOB were infiltrated by elevated fibroblasts and other immune-suppressive cells. 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: BMI ≥ 25 kg/m2, the elevated apoB containing lipoproteins indicated poor response to the combination of chemotherapy and ICIs in the in the NSCLC population. Further large-scale validations and experimental explorations are needed.

The role of immune checkpoints in cardiovascular disease

“…Another interesting self-antigen is apoliprotein B (apoB), the core protein of LDL cholesterol. A retrospective analysis in preprint found that lipoproteins high in apoB were risk factors for poor ICI response, especially in patients with ≥25 kg/m 2 BMI receiving combination therapy with chemotherapy ( Hu et al, 2022 ). While the interplay between apoB and IC remains to be elucidated, it is suggested that apoB-specific CD4 T cells can drive autoimmunity in atherosclerosis ( Marchini et al, 2021 ).…”