Mass Cytometry Reveals Classical Monocytes, NK Cells, and ICOS+ CD4+ T Cells Associated with Pembrolizumab Efficacy in Patients with Lung Cancer

Abstract

Purpose: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of non-small cell lung cancer (NSCLC), but predictive biomarkers of their efficacy are imperfect. The primary objective is to evaluate circulating immune predictors of pembrolizumab efficacy in advanced NSCLC patients. Experimental Design: We use high-dimensional mass cytometry (CyTOF) in baseline blood samples of advanced NSCLC patients treated with pembrolizumab. CyTOF data are analyzed by machine-learning algorithms (Citrus, tSNE) and confirmed by manual gating followed by principal component analysis (BGA). Results: We analyze 27 patients from the seminal KEYNOTE-001 study (median follow-up of 60.6 months). We demonstrate that blood baseline frequencies of classical monocytes, NK cells and ICOS+ CD4+ T cells are significantly associated with improved objective response rates, progression-free survival and overall survival (OS). Additionally, we report that a baseline immune peripheral score combining these three populations strongly predicts pembrolizumab efficacy (OS: HR=0.25 95%CI=0.12–0.51, p<0.0001). Conclusions: As this immune monitoring is easy in routine practice, we anticipate our findings may improve prediction of ICI benefit in advanced NSCLC patients.

Systemic CD4 Immunity and PD-L1/PD-1 Blockade Immunotherapy

“…Again, we showed that NK cells were, indeed, key effector cytotoxic cells that were associated to high myeloid diversity and increased monocytic cells [ 45 ]. A recent study corroborated the predictive power of CD4 T cells, NK cells and monocytes in a cohort of patients from the seminal KEYNOTE-001 study [ 157 ]. The application of multi-parametric flow cytometry highlighted the elevation of PD-1, PD-L1 and PD-L1 in T cells as biomarkers of worse survival [ 179 ].…”

“…The study by Kagamu and collaborators, together with our study, provides strong evidence that functional CD4 immunity is needed to achieve efficacious clinical responses in NSCLC [ 48 ]. While this manuscript was in revision, another study corroborated the utility of systemic CD4 T cell quantification as a biomarker of response to immunotherapy in patients from the landmark study KEYNOTE-001 [ 157 ].…”

Expression and prognosis of inducible T‐cell co‐stimulator and its ligand in Chinese stage I–III lung adenocarcinoma patients

“…Emerging literature reports that ICOS or ICOSL is dysregulated in various cancer types and contributes to tumor immune escape. 10 This study explored ICOS and ICOSL expression and their correlation with clinical outcomes in human NSCLC using TCGA data mining; also immunohistochemistry analysis was performed using freshly resected tumor tissue from selected lung cancer patients.…”

“…At present, the antitumor effect of the ICOS/ICOSL pathway has been recognized. Emerging literature reports that ICOS or ICOSL is dysregulated in various cancer types and contributes to tumor immune escape 10 . ICOS/ICOSL expressed in regulatory T‐cells (Tregs) within the tumor microenvironment largely influences T‐cell‐mediated tumor immune tolerance.…”

Top-of-the-art cytometry as a novel tool to aid in lung cancer immunotherapy

“…Having said that, CyTOF technology is still a valid and outstanding tool. Indeed, Rochigneux et al performed a high-dimensional mass cytometry examination of peripheral blood mononuclear cells (PBMCs) from NSCLC patients treated with pembrolizumab prior to start the treatment ( 13 ). The authors provided evidence that the blood baseline frequencies of classical monocytes, natural killer (NK) cells and inducible T-cell costimulatory ICOS + CD4 + T-cells were associated with pembrolizumab efficacy.…”