Significance of Quantitative Interferon-gamma Levels in Non-small-cell Lung Cancer Patients' Response to Immune Checkpoint Inhibitors

Abstract

Background/Aim: We aimed to study the association between the quantitative interferon-gamma (IFNγ) levels and clinical outcomes in non-small-cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs). Patients and Methods: Sample collection for IFN-γ release assay (IGRA) was performed within 14 days before treatment (T1), on day 22±7 (T3), and on day 43±7 (T4). The stored specimens over 10 IU/ml in IGRA were re-examined using the dilution method (with saline as the dilution medium). The patients were classified into Lower and Higher groups by 7.06 IU/ml as a cut-off of IFN-γ levels at T1. Results: Median progression-free survival in the Higher group was significantly longer than that in the Lower group. IFN-γ levels in the nonprogression disease group were significantly higher than those in the progression disease group. IFN-γ levels at T1 in patients with immune-related adverse events were significantly lower compared to those at T3. Conclusion: IFN-γ could be a biomarker for NSCLC patients receiving ICIs.Immune checkpoint Inhibitors (ICIs) are widely used as immunotherapy for a number of cancers. Cytotoxic Tlymphocyte-associated antigen 4 antibodies for melanoma were the first ICIs used in a clinical situation (1). After the programmed cell death-1 (PD-1) gene was cloned (2), an anti-PD-1 antibody (3) was also rapidly developed as one of the ICIs. Apart from treating melanomas, ICIs are being approved for different types of cancers, such as lymphomas (4) and gastric cancers (5).Non-small cell lung cancer (NSCLC) is one of the cancers usually treated with ICIs (6, 7). Programmed death-ligand 1 (PD-L1) is highly expressed in NSCLC and is the only biomarker that is used in the clinical practice to predict response to ICIs (8). However, this biomarker is not ideal because in some patients ICIs were less effective, even when PD-L1 expression level was high. In previous studies, many factors have been reported as biomarkers for ICIs response (9). However, none of the biomarkers were more effective than PD-L1. In our recent study (10), we examined the association between clinical outcomes of ICIs and levels of interferongamma (IFN-γ) release. We concluded that changes in the PD-1/PD-L1 axis by ICI treatment affected IFN-γ release by T lymphocytes, and IFN-γ levels could be a biomarker for the early detection of severe immune-related adverse events (irAEs), such as ICI-induced interstitial pneumonitis (ICI-IP), and for patient selection for ICI treatment. However, in our previous study (10) IFN-γ was examined qualitatively with an upper cut-off level of 10 IU/ml, while quantitative levels of IFN-γ in response to ICI are still unknown. As a result, the patients enrolled in our previous study were classified into three groups according to the IFN-γ levels at pre-treatment and on treatment, because the cut-off level of interferon-gamma release assay (IGRA) was 10 IU/ml. Because of this limitation in our previous study, we herein quantitatively re-examined the levels of IFN-γ >10 IU/ml using the diluti...

Significance of Pre-treatment Interferon-gamma Release in Patients With Non-small-cell Lung Cancer Receiving Immune Checkpoint Inhibitors

“…Huang et al (6) has previously reported that a higher pretreatment PHA-stimulated IFN-γ response (high-PHA) was associated with better survival among advanced NSCLC patients treated with chemotherapy. These findings are similar to those of our previous study (5), in which we suggested that Eruption 10 1 1 2 1 0 8 0 1 Thyroid dysfunction 7 0 0 3 0 0 4 0 0 Interstitial Pneumonitis 1 2 3 1 0 0 0 2 3 Colitis 1 3 1 0 0 1 1 3 0 Myositis 1 high-PHA, which may reflect a better immunological status, is associated with improved progression-free survival. Previous studies have identified several inflammation/ nutrition biomarkers as prognostic factors for cancer.…”

“…Firstly, IGR level directly examines the activity of viable T cells; therefore, it is an index of immune function. Secondly, IGR levels change dynamically during ICI-tx, depending on the immune status of the patients as shown in our previous studies (4,5). Thus, while other markers for ICI-tx efficacy are static biomarkers, IGR levels are dynamic, and more accurate.…”

“…The cut-off level of IGR in the PC was defined as 10 IU/ml, as described in the package inserts (12). Furthermore, the utility of the cut-off level of 7.06 IU/ml in the PC was reconfirmed, as established in our previous study (5). Latent tuberculosis or a past history of tuberculosis infection was determined based on the guidelines in the package inserts (12).…”

“…We showed changes in IGR in the PC after immune checkpoint inhibitor treatment (ICI-tx), and demonstrated the potential of IGR as a biomarker. Furthermore, our subsequent study (5) demonstrated that patients with a PC IGR level >7.06 IU/ml prior to ICI-tx had significantly longer progression-free survival than those with a PC IGR level 7.06 IU/ml. Huang et al (6).…”

T‐cell response to phytohemagglutinin in the interferon‐γ release assay as a potential biomarker for the response to immune checkpoint inhibitors in patients with non‐small cell lung cancer

“…9 Interferon-γ (IFN-γ) is released from T cells as part of their normal activation, and IFN-γ concentrations are reportedly related to ICI treatment response. 10 Furthermore, disruption of the IFN-γ receptor signaling pathway can lead to resistance to anti-PD-L1 therapy. 11 An IFN-γ releasing assay (IGRA) can be used to identify Mycobacterium tuberculosis based on T-cell production of IFN-γ in response to stimulation with tuberculosis-specific antigens (TBAgs).…”