Angiotensin-converting enzyme (ACE) inhibitor prescription affects non-small-cell lung cancer (NSCLC) patients response to PD-1/PD-L1 immune checkpoint blockers.

Angiotensin-converting enzyme (ACE) inhibitors are frequently used to treat hypertension and congestive heart failure. Preclinical data show that ACE plays a role on both innate and adaptive immune responses. Since interactions between ACE inhibitors and immune checkpoint inhibitors (ICIs) have not been reported, the aim of this study is to investigate the influence of ACE inhibitors on non-small cell lung cancer (NSCLC) patients treated with programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors. We conducted a retrospective cohort analysis of NSCLC patients treated with PD-1/PD-L1 inhibitors. Clinical and co-medication data as well as tumor biopsies were collected. Groups were defined according to patients' co-medications at the time of ICI initiation. Among the 178 patients included, 22 (13.1%) received ACE inhibitors. While baseline characteristics were similar in both groups, ACE inhibitors group had a shorter median PFS (Progression-Free Survival) compared to the control group: 1.97 vs. 2.56 months, p = .01 (HR = 1.8 CI95% 1.1-2.8). Using CIBERSORT, RNA sequencing suggested that tumors from the ACE inhibitors group had less M1 macrophages, activated mast cells, NK cells and memory activated T cells, thus suggesting an immunosuppressed state. In vitro, the ACE inhibitor, captopril, induced M2 marker at the cell surface of monocytes engaged into M1 differentiation. Thus, ACE inhibitors prescription concomitant to PD-1/PD-L1 inhibitors treatment seems to be associated with impaired outcome and with a tumor immunosuppressed state in patients with advanced NSCLC. These results should be validated in larger prospective cohorts.

Efficacy of immune checkpoint inhibitors in older patients with non-small cell lung cancer: Real-world data from multicentric cohorts in Canada and France.

BACKGROUND: Age-related immune remodelling is thought to be associated with resistance to immune checkpoint inhibitors (ICIs) in cancer. Patients older than 70 years, representing >50% of the population with non-small cell lung cancer (NSCLC) according to SEER database, are underrepresented in clinical trials exploring ICIs. The objective of this study was to determine if patients with NSCLC older than ≥70 years had inferior clinical outcomes with ICIs. METHODS: We conducted a retrospective analysis of 381 patients treated with anti-PD-(L)1 ICI for advanced NSCLC at the Dijon Cancer Center (n = 177), University of Montreal Hospital (n = 106) and Quebec Heart and Lung Institute (n = 98). Age was considered as a categorical variable. Patients' baseline characteristics were compared using the Chi-squared test. Survival curves were estimated by the Kaplan-Meier method and compared with the Log-rank test in a univariate analysis. Multivariate cox regression model was used to determine hazard ratios and 95% confidence intervals for progression-free survival (PFS) and overall survival (OS) between the groups, adjusting for other clinicopathologic features. RESULTS: Among 381 patients included, 335 (88%) received ICI after platinum chemotherapy. The median age was 66 (range 37-89) and 33% were older than 70 years of age. Considering age as a categorical variable, differences in age were not associated with PFS or OS. Subgroup analysis and multivariate cox regression did not reveal significant interaction of age with outcomes. ECOG performance status was the only significant factor in the three cohorts. CONCLUSIONS: Unlike previously described in the era of chemotherapy, age was not associated with outcomes in NSCLC patients treated with ICI.