Circulating Interleukin-4 Is Associated with a Systemic T Cell Response against Tumor-Associated Antigens in Treatment-Naïve Patients with Resectable Non-Small-Cell Lung Cancer

SIMPLE SUMMARY: Cytokines can increase the activity of T cells specific for tumor-associated antigens and thereby promote tumor-specific immune responses. In this study, cytokine profiles and T cell responses against 14 tumor-associated antigens were investigated in 36 treatment-naïve patients with resectable non-small cell lung cancer. Based on these results, preoperative serum interleukin-4 levels can play a role in predicting T cell responses specific for tumor-associated antigens and recurrence-free survival regardless of tumor stage. This is clinically relevant as patients with high preoperative serum interleukin-4 levels could be at high risk of postoperative tumor recurrence and, therefore, should be considered for adjuvant or neoadjuvant treatment. From this perspective, preoperative serum interleukin-4 levels may become a useful option to assess the risk of postoperative tumor recurrence in non-small-cell lung cancer. ABSTRACT: Spontaneous T cell responses to tumor-associated antigens (TAs) in the peripheral blood of patients with non-small-cell lung cancer (NSCLC) may be relevant for postoperative survival. However, the conditions underlying these T cell responses remain unclear. We quantified the levels of 27 cytokines in the peripheral blood and tumor tissues from treatment-naïve patients with NSCLC (n = 36) and analyzed associations between local and systemic cytokine profiles and both TA-specific T cell responses and clinical parameters. We defined T cell responders as patients with circulating T cells that were reactive to TAs and T cell nonresponders as patients without detectable TA-specific T cells. TA-specific T cell responses were correlated with serum cytokine levels, particularly the levels of interleukin(IL)-4 and granulocyte colony-stimulating factor (G-CSF), but poorly correlated with the cytokine levels in tumor tissues. Nonresponders showed significantly higher serum IL-4 levels than responders (p = 0.03); the predicted probability of being a responder was higher for individuals with low serum IL-4 levels. In multivariable Cox regression analyses, in addition to IL-4 (hazard ratio (HR) 2.8 (95% confidence interval (CI): 0.78–9.9); p = 0.116), the age-adjusted IL-8 level (HR 3.9 (95% CI: 1.05–14.5); p = 0.042) predicted tumor recurrence. However, this study included data for many cytokines without adjustment for multiple testing; thus, the observed differences in IL-4 or IL-8 levels might be incidental findings. Therefore, additional studies are necessary to confirm these results.