Impact of Renin–angiotensin System Inhibitors on the Efficacy of Anti-PD-1/PD-L1 Antibodies in NSCLC Patients

Abstract

Background/Aim: The Renin-Angiotensin system (RAS) induces immunosuppression in the tumor microenvironment, and RAS inhibitors (RASi) improve the tumor immune microenvironment. We evaluated the impact of RASi on the efficacy anti-programmed cell death-1/Ligand-1 (anti-PD-1/PD-L1) antibodies. Patients and Methods: This retrospective study analyzed non-small cell lung cancer (NSCLC) patients who received anti-PD-1/PD-L1 antibodies monotherapy as second-or later-line treatment. We classified patients into those with or without use of RASi. Results: A total of 256 NSCLC patients were included and 37 patients used RASi. The median PFS of patients treated with RASi was significantly longer than that of patients treated without (HR=0.59,. The median OS of patients treated with RASi tended to be longer than that of patients treated without (HR=0. 71, . Conclusion: The use of RASi was associated with a significantly longer PFS in NSCLC patients treated with anti-PD-1/PD-L1 antibodies. RASi use may enhance the efficacy of anti-PD-1/PD-L1 antibodies.Lung cancer is the leading cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancers. However, anti-programmed cell death-1/Ligand-1 (anti-PD-1/PD-L1) antibodies have improved the prognosis of NSCLC patients without oncogenic driver mutations. Nivolumab, pembrolizumab, and atezolizumab improved overall survival (OS) compared with docetaxel in pretreated NSCLC patients (1). Pembrolizumab prolonged OS in untreated NSCLC patients with positive PD-L1 expression compared with platinum-based chemotherapy (2, 3). Anti-PD-1/PD-L1 antibodies combined with chemotherapy improved progression-free survival (PFS) and OS compared with chemotherapy alone in untreated NSCLC patients with any PD-L1 expression (4-7). However, only some patients showed a long-term survival. Therefore, new strategies to enhance anti-PD-1/PD-L1 antibodies are needed.Medicines against common diseases such as gastritis, esophagitis, diabetes mellitus, and even hypertension [e.g., Renin-Angiotensin system inhibitors (RASi) including angiotensin-converting enzyme inhibitors (ACEi) and Angiotensin-II receptor blockers (ARB)] have been reported to have immunomodulatory effects (8-10). In the tumor microenvironment, RAS is expressed in cancer-associated fibroblasts, macrophages, and cancer cells (11). Recent studies showed that, in the tumor immune microenvironment, RAS induces immunosuppression while RASi improves it (10, 12). However, the association between RASi use and the efficacy of immunotherapy has not been fully investigated. Therefore, we evaluated the impact of RASi on the efficacy of anti-PD-1/PD-L1 antibodies in NSCLC patients. Patients and MethodsPatients and data collection. We retrospectively reviewed the electronic medical records of consecutive NSCLC patients who received anti-PD-1/PD-L1 antibody monotherapy as second-or later-line treatment at the Cancer Institute Hospital, Japanese Foundation for Cancer Research (Tokyo, Japan) between December 2015 and Jan...

Concomitant Medication Effects on Immune Checkpoint Inhibitor Efficacy and Toxicity

“…2.2 months without; HR = 0.59, p=0.008), and while there was a trend towards OS improvement, statistical significance was not achieved (OS = 22.6 months with vs . 14.7 months without; HR = 0.71, p=0.131) ( 32 ). The remaining studies reported a non-significant trend towards improved ICI efficacy with ARB use [Failing et al., 2016 ( 38 ): ORR = 38% with vs 28% without; OR = 2.01, p=0.22; Cortellini et al., 2020 ( 37 ): ORR = 42.9% with vs .…”

“…This ultimately leads to increased tumor plasticity and therapeutic resistance ( 29 – 31 ). Furthermore, the use of ACEi/ARBs may alter the TME through activating CD4 T cells, NK cells, and altering immunocytokines ( 28 , 32 , 33 ). However, some have demonstrated negative effects on the TME including enhanced M2 differentiation and activated mast cells, raising concerns about concurrent ACEi/ARB and ICI use ( 31 , 32 ).…”

Renin–angiotensin–aldosterone system inhibitors and survival in patients with hypertension treated with immune checkpoint inhibitors

“…Thus, there is scientific plausibility to support the potential for a beneficial effect of RAAS inhibitors in patients on an ICI. However, there are limited clinical data on the effect of RAAS inhibitors on outcomes among patients treated with an ICI [ 15 , 16 ]. Given the potentially significant impact on public health of these low-cost and relatively safe interventions, we performed a retrospective cohort study to evaluate the effect of the concurrent use of ICI and RAAS inhibitors in a large cohort of patients with cancer.…”

The PD-1 with PD-L1 Axis Is Pertinent with the Immune Modulation of Atrial Fibrillation by Regulating T Cell Excitation and Promoting the Secretion of Inflammatory Factors

“…The PD-1 and PD-L1 axis is a momentous member of this family, which can induce and maintain immune tolerance in external tissues under normal conditions. It has a positive role in preventing excessive tissue inflammation and also exerts a vital regulatory role in miscellaneous of infectious and autoimmune diseases [ 15 , 16 ]. After PD-1 binds to the ligand PD-L, they involved in the excitation, growth, and apoptosis of T cells and restrain the immunological response mediated by T cells.…”