Baseline Serum Cholesterol Levels Predict the Response of Patients with Advanced Non-Small Cell Lung Cancer to Immune Checkpoint Inhibitor-Based Treatment

Abstract

Although predictive markers of immune checkpoint inhibitor (ICI)-based treatments have been extensively studied, with the exception of programmed death ligand 1 (PD-L1), most are not widely used in the clinic due to poor effects or defective practicability. The aim of this study was to identify those patients with high baseline serum cholesterol who benefit from ICI-based treatments. Patients and Methods: Patients with advanced non-small cell lung cancer (NSCLC) treated at Ningbo Medical Center, Li Huili Hospital between August 2017 and December 2019 were enrolled in this retrospective study. The Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) were used to evaluate the efficacy of the ICIbased treatment. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier survival curves and compared using the log rank test. Univariate and multivariate analyses were conducted using the logistic regression analysis and Cox proportional hazards model. A receiver operating characteristic curve was created, and the area under the curve (AUC) was calculated to compare the predictive value of baseline serum cholesterol with PD-L1 expression for patient response to ICI-based treatment. Results: In our cohort of 169 NSCLC patients, the objective response rate (ORR) and disease control rate (DCR) of the treatment were significantly higher in patients with hypercholesterolemia (>5.18 mmol/L) than in those with hypocholesterolemia (ORR: 33.67% vs 14.08%, P=0.004; DCR: 68.37% vs 42.25%, P=0.001). The median PFS was 7.9 months in the hypercholesterolemia group, significantly longer than in the hypocholesterolemia group (4.4 months, 95% CI: 4.620-7.380, P<0.001). The median OS in the two groups were 11 months and 8 months, with 95% CIs of 8.980-10.420 (P<0.001). The AUC for the baseline level of cholesterol was 0.706 (P<0.001), while it was 0.643 (P=0.001) for PD-L1 expression. Conclusion:The baseline serum cholesterol level is predictive of a clinical benefit for advanced NSCLC patients who undergo ICI-based treatment, and hence it is a promising prognostic indicator for ICI-based treatment of NSCLC.

Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model

“…Hitherto, numerous biomarkers have been described, predicting response to checkpoint inhibition (2). Recently, cholesterol has been newly identified as a biomarker for the efficacy of PD-1 inhibition (3)(4)(5). Consistent with our own results, Perrone et al, Galli et al and Tong et al retrospectively showed, that baseline hypercholesterolemia was associated with better outcomes in patients treated with anti-PD-1 checkpoint therapy.…”

“…However, lipid metabolism is exhibiting contradictory roles in tumor immune response and besides other lipids, cholesterol emerges as a doubleedged sword in tumor immunity (66). In the context of cholesterol and immunotherapy, an association with response (3)(4)(5)(6) to therapy versus treatment failure (7,8) was delineated. Other authors interpreted the chain of causation differently and discussed chronic inflammation in first place, inducing T cell exhaustion, thus leading to cancer and hypercholesteremia as part of the metabolic syndrome, the latter again enhancing T cell exhaustion in the sense of a vicious circle (67).…”

‘Know thyself’ – host factors influencing cancer response to immune checkpoint inhibitors

“…A similar ‘cholesterol paradox’ is also emerging. For example, in a retrospective review of NSCLC patients receiving anti‐PD1 therapy, high total cholesterol correlated with both PFS and OS after adjustment for other covariates (such as gender, BMI, and smoking status) [70]. Intriguingly, this relationship was not seen in a chemotherapy‐treated cohort, suggesting potential ICI specificity.…”

Nomogram for predicting the prognosis of metastatic colorectal cancer patients treated with anti-PD1 therapy based on serum lipids analysis

“…Currently, increasing evidence has shown that serum lipids are also correlated with the prevalence and behaviors of various tumors, especially those of the digestive system, including GC, pancreatic cancer, and colorectal cancer [ 7 – 9 ]. Furthermore, studies have also demonstrated that serum lipids may be a promising marker for predicting the efficacy of ICI therapy in solid tumors, including non-small cell lung cancer [ 10 , 11 ], melanoma and renal cell carcinoma [ 12 ]. It has been demonstrated in mouse models that chemo- and immunotherapies can be co-loaded into synthetic HDL (sHDL), delivered locally to the tumor, and can be used to improve survival outcomes significantly compared to chemotherapy alone [ 13 ].…”