Combination therapy with expanded natural killer cells and atezolizumab exerts potent antitumor immunity in small cell lung cancer.

Despite an initial response to platinum-based chemotherapy, most patients with extensive stage of small cell lung cancer (SCLC) have a poor prognosis due to recurrence. Additionally, the benefit of immune checkpoint inhibitors is more modest than non-small cell lung cancer. Natural killer (NK) cells can directly eliminate cancer cells without prior sensitization; this is largely governed by inflammatory cytokines, which serve as killing signals to cancer cells. Here, we investigated whether the combination of NK cells plus atezolizumab, a fully humanized monoclonal antibody that specifically targets the protein programmed death-ligand 1 (PD-L1), has a synergistic effect against SCLC. NK cells were expanded and activated using irradiated K562 feeder cells in the presence of interleukin (IL)-2/IL-15/IL-21/41BB ligand for 14 days. Expanded and activated NK cells (eNK) were combined with atezolizumab and used to treat SCLC cells in both in vitro and in vivo studies. The results revealed increased PD-L1 expression in SCLC cells after the eNK challenge. eNK cells plus atezolizumab demonstrated increased cytotoxicity toward target SCLC cells, as evidenced by increased interferon-γ and tumor necrosis factor-α production, and higher levels of SCLC stem cell (CD44⁺CD90⁺) suppression. Combined treatment with eNK and atezolizumab more effectively inhibited SCLC tumor growth and significantly prolonged the survival of treated mice. Our findings revealed that combining eNK with atezolizumab strongly increased cytotoxicity, significantly inhibited SCLC tumor growth, and prolonged the survival of treated mice. These results provide a framework for developing a more advanced immunotherapeutic modality for future clinical trials for patients with SCLC.