Blood cytokine changes in patients with advanced NSCLC receiving immunotherapy

Immune checkpoint inhibitors (ICI) are routinely used for metastasized non-small-cell lung cancers (NSCLC), but reliable efficacy biomarkers are lacking. Serum samples of stage IV NSCLC patients at baseline (n=155) and after four therapy cycles (n=67) were analysed with cytometric bead arrays (CBA) for interleukin (IL)-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-17, interferon gamma (IFN-γ), tumour necrosis factor (TNF), intercellular adhesion molecule 1 (ICAM-1), interferon-gamma induced protein 10 (IP-10), vascular endothelial growth factor (VEGF), angiogenin, soluble CD40 ligand (sCD40L), CC motif chemokine ligand 5 (CCL5), granzyme A, and soluble TNF-receptor I (TNF-RI). Patients were treated with first-line (1L) immunotherapy (IO) alone or combined with chemotherapy (1L-CtxIO), stratified into long survivors (LS, progression-free survival [PFS]>200 days) vs. rapid progressors (RP, PFS<120 days), and complemented by age-matched non-cancer controls (n=15). Compared to the controls, NSCLC patients had higher serum IL-6 (22393.04 vs. 634.5 fg/ml, p<0.01), higher IP-10 (196.26 vs. 140.45 pg/ml, p<0.01) and higher CCL5 (16.84 vs. 12.25 ng/ml, p<0.05) at diagnosis. In addition, 1L-CtxIO patients had higher IL-8 (11058.77 vs. 650.81 fg/ml, p<0.001), IL-10 (1146.68 vs. 103.6 fg/ml, p<0.01), VEGF (182.41 vs. 86.64 pg/ml, p<0.01) and CCL5 (17.61 vs. 12.25 ng/ml, p<0.05), while 1L-IO patients had higher IL-6 (45172.84 vs. 634.5 fg/ml, p<0.01), ICAM-1 (1809.42 vs. 16.8 ng/ml, p<0.01), IP-10 (290.38 vs. 140.45 pg/ml, p<0.01), angiogenin (118.49 vs. 46.05 ng/ml, p<0.01) and TNFRI (2237.53 vs. 1251.6 pg/ml, p>0.01). LS had significantly lower TNFRI than RP patients (1716.44 vs. 2468.97pg/ml, p<0.05) at baseline. After 4 cycles of therapy, patients had lower IL-8 (8474.47 vs. 15384.64 fg/ml, p<0.05) and higher IP-10 (260.47 vs. 169.63 pg/ml, p<0.01) compared to baseline but no other significant differences were noted. Proinflammatory cytokines, such as IL-8 and IP-10 are increased in the serum of patients with advanced NSCLC at diagnosis and decrease under therapy. The potential role of baseline serum TNFRI as a predictive biomarker for immunotherapy warrants further investigation.