Project Summary
Squamous cell lung cancer, a subtype of non-small cell lung cancer (NSCLC), is the second most common type
of lung cancer. Also known as squamous cell carcinoma (SCC) of the lung, SCC is responsible for ~85,000 new
cases of lung cancer each year and ~50,000 deaths in the United States alone. SCC is distinct from the other
major subtype of NSCLC (adenocarcinoma) in terms of its histology, biomarker expression, genomic alterations,
immune microenvironment and response to therapy. SCC has limited therapeutic options that are confined to
chemotherapy and more recently, immunotherapy, which is only effective in a subset of patients. A major unmet
need for the treatment of SCC is the identification of new therapeutic targets and treatment strategies to combat
this disease. SCC has a unique histopathology and a complex microenvironment that is rich with desmoplastic
stroma, keratinization and immune cells. Specifically, tumor-associated neutrophils (TANs) are enriched in
mouse and human SCC, and neutrophil abundance correlates with poor prognosis and poor response to
immunotherapy. Relatively little is known about how TANs impact SCC tumor progression and therapeutic
response. It is notoriously difficult to model SCC in cell culture, which lacks the three-dimensional architecture
of tumors, an intact immune system, and vasculature. Genetically-engineered mouse models (GEMMs) provide
a complex living system that can highly recapitulate the human disease. Our laboratory pioneered the
development of the first SOX2-driven SCC GEMM. We recently developed a rapid new GEMM based on
alterations in Sox2/Lkb1/Nkx2-1 (SNL) where SCC tumors highly resemble the human disease in terms of
histopathology, genetics, and immune microenvironment. This new SNL model represents a unique immune-
competent tool to investigate how TANs shape tumor progression and therapeutic response. The objective of
this study is to elucidate the role of TANs in squamous lung cancer development, progression and response to
therapy. We hypothesize that TANs promote squamous cell fate by increasing reactive oxygen species (ROS),
which are implicated in tumor transdifferentiation, and by promoting neutrophil extracellular traps (NETosis). To
test these hypotheses, we will: 1) Determine the mechanism by which TANs alter tumor cell fate. 2) Determine
whether TANs promote squamous lung cancer progression via ROS and/or NETosis. 3) Determine whether
neutrophil depletion enhances response to chemotherapy and/or immunotherapy. This approach is innovative
because we will employ: 1) our novel immune-competent SCC GEMM that recapitulates key features of the
human disease, 2) neutrophil depletion strategies that are in clinical trials, and 3) state-of-the-art technologies
including single cell RNA-sequencing and natural cancer-associated inhibitors of NETosis. This research is
significant because TAN function in SCC is almost completely unexplored and TANs may represent a new
therapeutic target for this intractable disease.