Blood Biomarkers of Response to Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of non-small cell lung cancer (NSCLC), either used in monotherapy or in combination with chemotherapy. While some patients achieve durable responses, some will not get benefit from this treatment. Early identification of non- responder patients could avoid unnecessary treatment, potentially serious immune-related adverse events and reduce treatment costs. PD-L1 expression using immunohistochemistry is the only approved biomarker for the selection of patients that can benefit from immunotherapy. However, application of PD-L1 as a biomarker of treatment efficacy shows many deficiencies probably due to the complexity of the tumor microenvironment and the technical limitations of the samples. Thus, there is an urgent need to find other biomarkers, ideally blood biomarkers to help us to identify different subgroups of patients in a minimal invasive way. In this review, we summarize the emerging blood-based markers that could help to predict the response to ICIs in NSCLC.

Plasmacytoid Dendritic Cell, Slan+-Monocyte and Natural Killer Cell Counts Function as Blood Cell-Based Biomarkers for Predicting Responses to Immune Checkpoint Inhibitor Monotherapy in Non-Small Cell Lung Cancer Patients

“…In this context, significant efforts have been made to identify potential blood-based biomarkers that, compared to tumor microenvironment-related biomarkers, would be non-invasive and relatively cheap [26][27][28]. However, to date, the predictive role of different blood-based biomarkers remains unclear, mostly due to the lack of standard detection/analysis methods and to the fact that most studies have focused on the evaluation of single, or of very few, blood-based biomarkers within the same patient cohort.…”

“…However, several limitations, including the intratumoral heterogeneity and the invasiveness of tumor biopsies that cannot be repeatedly performed to monitor early disease response in most patients, render the TPS and TMB as defective and controversial biomarkers [24,25]. On the other hand, monitoring blood-based biomarkers is non-invasive and can be repetitively performed, providing insights to the patient's immune status [26][27][28]. In the past few years, the number of studies that have evaluated different blood-based parameters as potential predictive biomarkers for ICI therapy in NSCLC patients has grown exponentially [29][30][31][32].…”

“…In the past few years, the number of studies that have evaluated different blood-based parameters as potential predictive biomarkers for ICI therapy in NSCLC patients has grown exponentially [29][30][31][32]. These blood-based biomarkers include parameters such as the serum levels of soluble systemic immune/inflammatory molecules (i.e., the serum levels of lactate dehydrogenase (LDH), C-reactive protein (CRP) or soluble PD-L1), tumor-cell-related markers (i.e., blood-based tumor burden, circulating tumor cells and tumor DNA) or the dynamic changes in the frequency/number of various circulating immune cell subsets [26,[29][30][31][32]. In particular, regarding blood-cell-based biomarkers, several studies have evaluated parameters such as the neutrophil-to-lymphocyte ratio (NLR) or the total cell count/frequency of the different subpopulations of lymphocytes or innate immune cells as potential predictive biomarkers for ICI monotherapy in NSCLC patients [27,29,31].…”

Linkage between Psychological Factors and Response to Immune Checkpoint Inhibitor Therapy: A Preliminary Study

“…Cytokines are a diverse group of small-cell signaling proteins, have a prominent role in regulating immune activity, and control inflammatory and anti-inflammatory processes [16]. Cytokines can induce checkpoint expression and responses to ICI therapy [16][17][18][19]. Several cytokines in peripheral blood, especially pro-inflammatory cytokines, usually increase after ICI therapy [18].…”

“…Several cytokines in peripheral blood, especially pro-inflammatory cytokines, usually increase after ICI therapy [18]. Peripheral cytokines were found to predict the outcome of ICI treatment [10,17,19,20]. For example, higher levels of pro-inflammatory cytokines (e.g., IL-6, IL-8, TNFα) in peripheral blood before treatment were usually found to predict worse responses in various cancer types, including metastatic non-small-cell lung cancer and melanoma [10,[21][22][23].…”