Harnessing natural killer immunity in metastatic small cell lung cancer.

Abstract

Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer and though most patients initially respond to platinum-based chemotherapy, resistance rapidly develops. Immunotherapy has promise in the treatment of lung cancer, however SCLC patients exhibit poor overall responses highlighting the necessity for alternative approaches. Natural killer (NK) cells are an alternative to T cell-based immunotherapies, that do not require sensitization to antigens presented on the surface of tumor cells. We investigated the immunophenotype of human SCLC tumors by both flow cytometry on fresh samples and bioinformatic analysis. Cell lines generated from murine SCLC were transplanted into mice lacking key cytotoxic immune cells. Subcutaneous tumor growth, metastatic dissemination and the activation of CD8+ T and NK cells were evaluated by histology and flow cytometry. Transcriptomic analysis of human SCLC tumors revealed heterogeneous immune checkpoint and cytotoxic signature profiles. Utilizing sophisticated genetically engineered mouse models, we demonstrated that the absence of NK cells, but not CD8+ T cells, significantly enhanced metastatic dissemination of SCLC tumor cells in vivo. Moreover, hyperactivation of NK cell activity through augmentation of IL-15 or TGF-β signaling pathways ameliorated SCLC metastases, an effect which was enhanced when combined with anti-PD1 therapy. These proof-of-principle findings provide a rationale for exploiting the anti-tumor functions of NK cells in the treatment of SCLC patients. Moreover, the distinct immune profiles of SCLC subtypes reveal an unappreciated level of heterogeneity that warrants further investigation in the stratification of patients for immunotherapy.