Soluble Immune Checkpoints as Prognostic Biomarkers in Small Cell Lung Cancer Patients Treated with Chemotherapy and Anti-PD-L1

Soluble immune checkpoints (sICs) have emerged as potential biomarkers in various cancers. However, their role in extensive-stage small cell lung cancer (ES-SCLC), an aggressive tumor type with limited therapeutic options and poor prognosis, remains poorly characterized. We analyzed 14 circulating sICs, leukocyte–platelet (PLT) complexes, and PD-L1 surface expression in ES-SCLC patients treated with chemoimmunotherapy (n = 41) prior to treatment and healthy donors (HD, n = 10). We assessed their associations with clinical and demographic factors and performed survival analyses using Kaplan–Meier and log-rank tests. Levels of soluble (s) PD-L1, PD-L2, BTLA, HVEM, TIM-3, and CD27 were higher in plasma from ES-SCLC patients compared to those from HD (p < 0.05). Patients with liver metastases exhibited higher sIC levels, and a multivariate model demonstrated discriminative power. Network analyses revealed distinct patterns of immune dysregulation between ES-SCLC and HD. We observed correlations among sICs and leukocyte–PLT complexes and leukocyte PD-L1 expression, indicating links between systemic immune status and tumor–immune interactions. Furthermore, increased concentrations of sTIM-3, sCD27, sHVEM and sPD-L1 were associated with a poor prognosis. Overall, sICs reflect relevant clinical, prognostic, and immunological features in ES-SCLC. Their plasma measurement could aid in non-invasive patient stratification regarding liver metastases and survival risk.