Lung cancer is the most common cancer and the leading cause of cancer death worldwide, with an estimated 2.1 million new cases and 1.8 million deaths in 2018. Although small cell lung cancer (SCLC) is the most aggressive type of lung cancer, it shows high response rates to chemotherapy in early lines of therapy. Unfortunately, it is associated with rapid recurrence and relatively poor prognosis. Over the last few years, considerable progress has been made in cancer immunotherapy. One of the most promising ways to activate therapeutic antitumor immunity is via blockade of immune checkpoints, such as cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1). Immune checkpoint inhibitors show promise as SCLC therapeutics. The overall expectation for immuno-oncology is high, and the outcomes of trials will hopefully reveal a variety of treatment options for SCLC patients. In this review, we discuss the discovery of new immune inhibitory and stimulatory pathways and rational combination strategies to explain the role of immunotherapy in SCLC and its future opportunities and challenges.

IntroductionImmune-based and antibody-drug conjugate therapies have shown promise in the treatment of patients with small cell lung cancer (SCLC). However, better predictive biomarkers are needed for selection of the appropriate SCLC patients for these advanced therapies and also for evaluation of the efficacy of these treatments.ObjectiveThe aim of this study was to examine the expression of delta-like protein 3 (DLL3), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), and mesothelin (MSTN) in patients with SCLC and compare them with those patients’ clinical characteristics.MethodsImmunohistochemical analyses of DLL3, CTLA-4 and MSTN expression were performed in 38 samples from patients with SCLC.ResultsWe found that positive expression in patients of the biomarkers was as follows: for DLL3, 100% (38/38), for CTLA-4, 89.5% (36/38) and for MSTN 81.5% (31/38). The median survival time was 17.9 months in the DLL3 high expression group and 23 months in the DLL3 low expression group. Patients with a high expression of DLL3 showed a poorer prognosis than those with a low expression of DLL3 (HR=3.4; 95% CI, 1.34–8.6; p=0.01).ConclusionThe expression of DLL3, CTLA-4 and MSTN was not correlated with patients’ age, sex, smoking status, stage, and tumor metastasis. The fact that there was a higher expression of DLL3, CTLA-4, and MSTN in SCLC suggested that these molecules could be used as predictive biomarkers for SCLC.