A cohort study of circulating biomarkers to predict the efficacy and prognosis of immune combination therapy in non-small-cell lung cancer.

Background: Immune checkpoint inhibitors (ICIs) bring significant clinical benefits to non-small-cell lung cancer (NSCLC), and convenient peripheral blood markers are still lacking. Human circulating cytokines play an important role in tumor growth and metastasis, and exploring their value in NSCLC immunotherapy helps to achieve precise treatment of patients.

Methods: This study was a mixed design of prospective blood collection and retrospective data collection. Patients with NSCLC who received the first ICI combined with chemotherapy were included, and plasma samples were collected at baseline and after 2 cycles of treatment. MILLIPLEX MAP technology was used to detect the levels of a panel of cancer biomarkers and to explore the predictive potential of cytokines for survival and treatment response in such patients.

Results: Baseline blood samples were collected from 79 NSCLC patients in this study, and survival analysis showed that high expression of 4 cytokines, carbohydrate antigen 125 (CA125), cytokeratin 19 fragment (CYFRA 21-1), human epididymis protein 4 (HE4), and hepatocyte growth factor (HGF), was associated with shorter overall survival (OS) and progression-free survival (PFS), low levels of stem cell factor (SCF) tended to have better OS than patients with high levels of SCF, and multivariate Cox regression showed that high levels of HGF were independent risk factors for OS (HR = 1.92, 95% CI: 1.02-3.70, P = .042) and PFS (HR = 3.23, 95% CI: 1.75-5.88, P < .001). HGF was more predictive of 1-year survival and 6-month PFS than programmed death ligand 1 expression. In addition, we collected blood samples from 53 patients after 2 cycles of treatment, CYFRA 21-1, HGF, interleukin-8 (IL-8), and tumor necrosis factor-related apoptosis-inducing ligand were associated with patient survival, and patients with increased HGF after treatment had shorter survival. In patients whose tumors responded to treatment, CA125 and CYFRA 21-1 levels increased from baseline, whereas soluble apoptosis-related factor (sFas) levels decreased.

Conclusions: Soluble cytokines, especially HGF, have certain clinical value in immunotherapy combination therapy and prognosis of NSCLC patients and are worthy of validation in a larger prospective cohort and exploration of their potential mechanisms.