The predictive value of the interferon-γ release assay for chemotherapy responses in patients with advanced non-small-cell lung cancer

Highlights

• Phytohemagglutinin-stimulated IFN-γ (PSIG) level may represent one’s immune status.

• Patients with lower pre-chemotherapy PSIG levels had shorter survival time.

• Patients with lower pre-chemotherapy PSIG levels had lower disease control rate.

• An adequate immune function may be a prerequisite for chemotherapy response.

Abstract

Objectives

IFN-γ takes part in immunologic responses to cancer and its interactions with chemotherapy have also been described. Our previous study had showed an association between phytohemagglutinin (PHA)-stimulated IFN-γ (PSIG) response and overall survival in patients with advanced non-small-cell lung cancer (NSCLC). Here, we aimed to evaluate the correlation between PSIG and chemotherapy responses.

Materials and methods

From January 2011 to August 2012, 340 newly diagnosed patients with lung cancer were enrolled in a prospective latent tuberculosis observational study. Patients with advanced NSCLC who were treated with chemotherapy were included in this analysis. An IFN-γ release assay (IGRA) was used to evaluate pre-treatment PSIG levels. Patients were grouped into low and high PHA response groups according to their PSIG levels. Their demographic characteristics, tumor responses, and survival rates were investigated.

Results

Eighty-four patients were enrolled. The chemotherapy response rates in the high and low PHA response groups were 45.2% and 35.7% (p = 0.190), respectively. The disease control rate in the high PHA response group was 76.2%, versus 52.4% in the low PHA response group (p = 0. 023). In multivariate analysis, PHA response was an independent predictor of disease control (odds ratio = 3.017, 95% confidence interval = 1.115–8.165). The Kaplan-Meier method demonstrated both longer progression-free survival (p = 0.008) and overall survival (p = 0.003) in the high PHA response group.

Conclusions

A higher pre-treatment PSIG response, obtained using the IGRA, was associated with better disease control rate and survival among patients with advanced NSCLC treated with chemotherapy.

Introduction

Lung cancer is one of the most common and fatal diseases worldwide [1], and yet only 15 ∼ 20% patients are diagnosed early on in their disease course [2]. For advanced stage non-small-cell lung cancer (NSCLC), there are several treatment options including conventional chemotherapy, targeted therapy, and immunotherapy. However, how to tailor treatment to achieve the best response and avoid unnecessary toxicities remains a challenge for both clinicians and scientists. Unlike targeted therapy and immunotherapy, there is no clinically available test to predict chemotherapy responses.

Interferon-gamma (IFN-γ), a cytokine that was originally discovered to participate in the host response to viral infection, has recently been identified to also take part in cancer-related immunity. Critchley-Thorne et al. had originally proposed that impaired IFN signaling might be a common defect in human cancer [3]. Legrie et al. furthered this observation by using patient-derived xenografts to demonstrate that activation of tumor cells’ IFN/STAT1 signaling was related to better chemotherapy responses [4]. These studies suggested a close interaction among IFN, chemotherapy responses, and cancer-related immunity.

In our previous study [5], we surveyed the prevalence and the predictors of latent tuberculosis infection (LTBI) in 340 newly diagnosed patients with lung cancer of all stages in Taiwan using IFN-γ release assays (IGRAs) and found that approximately one-quarter of them have LTBI. Interestingly, in addition to lower body mass index and advanced disease stage, we found that indeterminate results on the IGRA was an independent prognostic factor. The indeterminate results on the IGRA generally reflected the patients’ impaired immune function by showing inadequate IFN-γ secretion from peripheral lymphocytes in response to the stimulatory molecule, phytohemagglutinin (PHA), in vitro. This finding had drawn our interests into examining these phenomena further. We hypothesized that the lymphocyte function, evaluated by the IFN-γ response to PHA stimulation, might predict overall chemotherapy responses. The aim of the current study was to investigate the association between PHA-stimulated IFN-γ (PSIG) secretion from patients’ peripheral lymphocytes and the chemotherapy responses in patients with advanced stage NSCLC.