IMMUNOLOGICAL LANDSCAPE OF NON-SMALL CELL LUNG CANCER: OPPORTUNITIES FOR INTERVENTION?

Lung cancer is the leading cause of annual cancer related mortality in the United States. More than 150,000 people in the U.S. will die from lung cancer this year which will lead to roughly as many deaths as breast, prostate, colon, and pancreatic cancers combined. Lung cancer is also of global concern as tobacco and cigarette use, a significant known risk factor, in developing countries have risen significantly. Stage II and III non-small cell lung cancer (NSCLC) patients often have a 5-year disease free survival of less than 50% even after surgical resection and post-operative chemotherapy and a dismal 5% overall survival for patients with stage IV metastatic disease. Even with the advent of PD-1/PDL-1 checkpoint blockade immunotherapies, only about 20% of patients are responsive to the treatment. This limited scope of success may be due to our lack of understanding the immune landscape of NSCLCs. Therefore, we set out to characterize the immune composition from surgical lung resections via flow cytometry. We found that NSCLCs have a diverse set of checkpoint inhibitor and co-stimulatory molecules expressed by T cells, including PD-1, TIM-3, and TIGIT. Interestingly, even though PD-1 was elevated compared to a normal donor, the expression level was lower than either breast or melanoma tumor samples. We also discovered that PD-1 heavily correlates with co-expression of other checkpoint inhibitor molecules. In our regulatory T cell analysis, FoxP3+ populations have a profound presence in these lung tumors suggesting there is a highly suppressive environment for tumor infiltrating lymphocytes (TILs). Our lung resection screenings furthermore suggests a dynamic range of both frequency and proportion of CD3-CD56+ natural killer (NK) cells. Finally, our data indicates there is a large population of CD11b+CD33+ myeloid-derived suppressor cells (MDSCs) in the tumors, with a diverse range of arginase-1 expression, a functional marker for MDSCs. Altogether, these findings in concert suggest there are potential goldmine of opportunities to target molecules on different immune cell populations. This multi-modal approach, directing combination of immunotherapies that influences multiple immune compartments yet complement each other, may have significant implications for future clinical studies.