Heme-oxygenase-1: A potential biomarker for ICIs in patients with advanced lung cancer.
Authors: Biello Federica , Martini Veronica , Borra Gloria , Genestroni Silvia , Branni Carmen , Gennari Jacopo , Duka Ilba , Ben Ayed Rahma , Bettini Sabrina , Gobbato Simone , Negrini Letizia , Alsati Rami , Invernizzi Francesca , Sica Antonio , Gennari Alessandra 
Published: July 2024

e20505 Background: Immune checkpoint inhibitors (ICIs) significantly improved the outcome in patients with lung cancer. However, heterogeneity in clinical benefit and absence of a reliable biomarker still represent an unmet need. Metabolic reprogramming plays a critical role in cancer behaviour. In particular, heme-ossigenase-1 (HO-1) expression on monocytes may have a role in treatment resistance. Methods: “ImmunoEGA” is a prospective, observational study in patients with advanced tumors, treated with ICIs at the ‘Maggiore della Carità’ Hospital in Novara, IT. Overall, 150 patients have been recruited from 2018 to 2023; of these, 122 were affected by lung cancer. In the present study we analysed monocytes subpopulations and HO-1 expression on blood samples collected from 34 patients at the following time points: baseline, at time of disease evaluation and at disease progression (PD). Monocytes were classified into three different phenotypes based on CD14 and CD16 expression: classical (CD14+CD16–), non-classical (CD14-CD16+) and intermediate (CD14+CD16+). The primary endpoint was treatment outcome in terms of progression free survival (PFS) and/or overall survival (OS). Results: At baseline, the frequency of classical monocytes was higher as compared to non-classical and intermediate subgroups, independently from type of response (mean percentage: 48,4% vs 7,8 vs 23,9%; p < 0.0001). Compared with baseline, we observed a relative increase in the frequency of classical (54,8 vs. 56,9) and intermediate (19,5 vs. 21,1) monocytes in patients with stable disease (SD) at the time of best response. Conversely, patients with PD showed an increase in non-classical (6,3 vs.14,1) and intermediate monocytes (26,3 vs. 30,9). In patients with partial response (PR) all monocyte subgroups increased proportionally (classical: 40,6 vs. 45,5; intermediate 24,2 vs. 25,9; non-classical 7,8 vs. 13,6). A higher baseline frequency of classical monocyte positively correlated with PFS (14 vs 6.5 m, p = 0,0171); these data were not observed for OS. No differences were detectable in HO-1 expression across monocytes subtypes at baseline and at the time of best response (SD or PR). Conversely, HO-1 expression showed an increasing trend across monocytes subpopulations at PD. Lower on classical (mPFS 15 vs 7 m, p = 0,0186) and intermediate monocytes (mPFS 15.5 vs 6.5 m p = 0,0057) at baseline correlated with better PFS. Patients with lower HO-1 expression on intermediate monocytes at baseline had a better outcome (OS 18 vs 11.5 m, p = 0.0378). Conclusions: In patients with lung cancer, higher frequency of classical monocytes and lower HO-1 expression in intermediate and classical monocytes predict better outcomes with ICI. The expression of HO-1 in classical and intermediate monocytes significantly increases at PD, suggesting its implication in promoting cancer progression. HO-1 expression could be used as a biomarker of immunotherapy benefit.