Studies of human NSCLC tissue, matched non-adjacent lung tissue, and peripheral blood specimens performed in our lab over the past five years have allowed us to identify four fundamental categories of immune response to lung cancers. These categories include previously described “inactive” or “cold” tumors, “active” or “hot” tumors, and a novel myeloid-enriched subgroup that we have labeled “excluded.” Excluded tumors are enriched in myeloid lineage cells, particularly neutrophils, do not display the anti-tumor IFNg signature, and have a paucity of T cells within the malignant component of tumor. We are currently focusing our studies on human NSCLC subjects who have received immune checkpoint inhibitor therapy with the goal of identifying the dominant myeloid lineage signature and effector molecules mediating treatment failures.
The Houghton Lab has been actively studying the role of the neutrophil lineage in solid tumors for the past 15 years. These efforts have resulted in seminal studies involving the recruitment of neutrophils to lung cancer, the role of neutrophil elastase with the lung TME, and the essential role that neutrophils play in mediating the immune “excluded” phenotype frequently identified in NSCLC. Current efforts in the lab are focused on identifying the exact mechanisms by which neutrophil lineage cells mediate the “excluded” phenotype, the relative contribution of PMN vs. PMN-MDSC to tumor growth and invasiveness, and the identification of novel therapeutic strategies targeting the neutrophil lineage to enhance the efficacy of immune checkpoint blockade.
During studies of the immune cell composition of NSCLC, we observed that CD19+ B lymphocytes displayed the largest increase in cellular content when comparing the cellular content in non-adjacent lung tissue to that within the tumor mass. B cells represent just ~0.5% of CD45+ cells in lung tissue but jump to ~4% of CD45+ cells in NSCLC tissues. These B cells are frequently located within lymphoid aggregates or the tumor stroma and generate antibodies, some of which are tumor specific. We have leveraged this concept to study circulating plasma antibodies against tumor antigens for the purpose of lung cancer early detection. In conjunction with the Lampe Lab at Fred Hutch, we are developing multi-parameter early detection prediction rules based on novel circulating auto-antibodies and other proteomic markers.