Modulation of the migratory dendritic cell tumor-immune microenvironment as a novel treatment for SMARCA4-mutant lung adenocarcinoma using combined anti-ICAM1 and anti-PD-L1 therapies

Abstract: Disease progression/ metastasis is responsible for over 90% or 100,000 deaths in patients diagnosed with lung adenocarcinoma (LAD). Metastasis suppressor 1 (MTSS1) is a metastasis suppressor protein critical for maintaining cell cytoskeletal integrity. Its role in lung adenocarcinoma pathogenesis is largely unknown. We have shown that loss of MTSS1 expression is correlated with poor survival in lung adenocarcinoma patients and that re-expression of MTSS1 inhibits in-vivo metastasis. Our recent investigation has demonstrated MTSS1 expression is critical for disease progression in SMARCA4-mutant LAD, an aggressive subtype of lung adenocarcinoma with no targeted therapies. In this proposal, we will characterize a novel mechanism and targetable pathway mediated by MTSS1 in SMARCA4-mutant lung adenocarcinoma. Using whole transcriptome sequencing/pathway analysis, we have discovered MTSS1 expression decreases myeloid cell tumor microenvironment pathway gene expression in SMARCA4-mutant LAD. We have discovered a novel mechanism by which MTSS1 inhibits NF-κB activity in SMARCA4-mutant LAD. ICAM1 was the most significantly downregulated protein by MTSS1 in SMARCA4-mutant LAD and is an important surface marker of the metastasis phenotype in SMARCA4-mutant LAD. Our preliminary in-vivo studies showed that anti-ICAM1 blocking antibody reduces disease progression in SMARCA4-mutant LAD and also upregulated migratory dendritic cell population in the tumor microenvironment. Migratory dendritic cells are robust tumor antigen presenting cells that also upregulates PD-L1 expression in the tumor microenvironment. Aim 1 will evaluate the synergistic effect of anti-ICAM1 and anti-PD-L1 therapy on SMARCA4-mutant LAD using an immunocompetent CD34+ humanized orthotopic mouse model. Aim 2 will further characterize the alterations of myeloid cells within the tumor microenvironment as well as the single cell gene transcriptional changes following this novel combined therapeutic approach in SMARCA4-mutant LAD. The novel treatment strategy proposed could provide an effective therapy for a lung adenocarcinoma subtype which is resistant to currently available treatments.