Association between serum levels of 12 different cytokines and short-term efficacy of anti-PD-1 monoclonal antibody combined with chemotherapy in advanced gastric cancer

Abstract

Background: Gastric cancer (GC) is characterized by aggressive tumor growth and poor prognosis. The benefits of targeted anti-programmed death receptor 1 (PD-1) monoclonal antibody combined with chemotherapy have not yet been characterized. The tumor microenvironment and circulating factors have garnered interest as possible predictors of response and prognosis. The aim of this study was to evaluate whether cytokine levels in the serum of patients were related to tumor response to anti-PD-1 monoclonal antibody combined with chemotherapy and survival in advanced GC.

Materials and methods: Preoperative serum samples were collected from patients with GC (n = 52) and healthy individuals (n = 31). The levels of 12 different cytokines were measured using a multiple microsphere flow immunofluorescence assay. The association between cytokine levels and clinical response was analyzed using nonparametric Wilcoxon matched-pair ranked tests. Progression-free survival (PFS) time for all patients was recorded via evaluation of imaging results and follow-up via telephone. Kaplan-Meier and log-rank tests were used to plot survival curves.

Results: The levels of interleukin (IL)-6, IL-1β, interferon (IFN)-γ, IL-17, and IL-12p70 in the control group were significantly lower than those in the GC group (p = 0.0002, p = 0.0065, p = 0.0003, p = 0.0303, and p = 0.0295, respectively). The level of IL-4 was significantly higher in healthy individuals than that in patients with GC (p = 0.0201). The cytokine levels in the good responder group were higher than those in the poor responder group before therapy. Patients treated with immunochemotherapy showed an overall reduction in all cytokine levels after treatment initiation. A high baseline level of IFN-γ was associated with a better prognosis. However, high IL-6 levels in patients after two cycles of immunochemotherapy indicated resistance. High IL-4 levels in patients treated with four cycles of immunochemotherapy were associated with better PFS.

Conclusions: Our study suggests that low levels of IFN-γ before immune checkpoint inhibitor treatment may be useful for the detection of a poor immunological status. Hence, a reduction in IL-6 levels is predictive of a longer PFS, and increased IL-4 levels are predictive of a good response. IL-4 and IL-6 may, therefore, serve as promising circulating predictive biomarkers for patients who can benefit from anti-PD-1 monoclonal antibodies administered in combination with chemotherapy.

Keywords: Anti-PD-1 monoclonal antibody; Cytokines; Gastric cancer; Immunochemotherapy; Progression-free survival.