Highlights d Multiple SCLC molecular subtypes arise from a neuroendocrine cell of origin d MYC drives the NEUROD1 + and YAP1 + subtypes of SCLC in a temporal evolution d MYC directly activates NOTCH signaling to reprogram neuroendocrine fate d Multiple SCLC molecular subtypes are present within individual human tumors

SUMMARY The major types of non-small cell lung cancer (NSCLC) - squamous cell carcinoma and adenocarcinoma - have distinct immune microenvironments. We developed a genetic model of squamous NSCLC based on overexpression of the transcription factor Sox2, which specifies lung basal cell fate, and loss of the tumor suppressor Lkb1 (SL mice). SL tumors recapitulated gene expression and immune infiltrate features of human squamous NSCLC, including enrichment of tumor-associated neutrophils (TANs) and decreased expression of NKX2–1, a transcriptional regulator that specifies alveolar cell fate. In Kras-driven adenocarcinomas, mis-expression of Sox2 or loss of Nkx2–1, led to TAN recruitment. TAN recruitment involved SOX2-mediated production of the chemokine CXCL5. Deletion of Nkx2–1 in SL mice (SNL) revealed that NKX2–1 suppresses SOX2-driven squamous tumorigenesis by repressing adeno-to-squamous transdifferentiation. Depletion of TANs in SNL mice reduced squamous tumors, suggesting that TANs foster squamous cell fate. Thus, lineage defining transcription factors determine the tumor immune microenvironment, which in turn may impact the nature of the tumor.

The outcomes of patients with SCLC have not yet been substantially impacted by the revolution in precision oncology, primarily owing to a paucity of genetic alterations in actionable driver oncogenes. Nevertheless, systemic therapies that include immunotherapy are beginning to show promise in the clinic. Although, these results are encouraging, many patients do not respond to, or rapidly recur after, current regimens, necessitating alternative or complementary therapeutic strategies. In this review, we discuss ongoing investigations into the pathobiology of this recalcitrant cancer and the therapeutic vulnerabilities that are exposed by the disease state. Included within this discussion, is a snapshot of the current biomarker and clinical trial landscapes for SCLC. Finally, we identify key knowledge gaps that should be addressed to advance the field in pursuit of reduced SCLC mortality. This review largely summarizes work presented at the Third Biennial International Association for the Study of Lung Cancer SCLC Meeting.