Potential immune escape mechanisms underlying the distinct clinical outcome of immune checkpoint blockades in small cell lung cancer

Small cell lung cancer (SCLC) is one of the deadliest cancer types in the world. Despite the high response rate to frontline platinum-containing doublets, relapse is inevitable for the majority of patients and the prognosis is poor. Topotecan, which has limited efficacy, has remained the standard second-line therapy for approximately three decades. Although SCLC has a high mutation burden, the clinical efficacy of immune checkpoint blockades (ICBs) in SCLC is far less pronounced than that in non-small cell lung cancer (NSCLC). Only atezolizumab in combination with chemotherapy improved overall survival over chemotherapy alone in the phase III CheckMate 133 trial and has recently received FDA approval as first-line therapy. Most studies concerning ICBs in SCLC are limited to early-phase studies and found that ICBs were not superior to traditional chemotherapy. Why is there such a large difference between SCLC and NSCLC? In this review, comparative analyses of previous studies indicate that SCLC is even more immunodeficient than NSCLC and the potential immune escape mechanisms in SCLC may involve the low expression of PD-L1 and the downregulation of major histocompability complex (MHC) molecules and regulatory chemokines. In consideration of these immune dysfunctions, we speculate that chemotherapy and radiotherapy prior to immunotherapy, the combination of ICBs with antiangiogenic treatment, and selecting tumor mutation burden in combination with PD-L1 expression as biomarkers could be promising strategies to improve the clinical efficacy of immunotherapy for SCLC.