Lung cancer is the leading cause of cancer related deaths for both men and women in the United States. Non-small cell lung cancer subset is genomically very well characterized with targeted treatment options available for certain subsets such as EGFR mutation, ALK, and ROS genetic fusions. Targeted treatment as such are effective until tumors develop acquired resistance.
Our lab studies the molecular drivers of tumor immune escape.
Despite the antigenic potentialities of tumors, they are able to grow in immunocompetent individuals due to activation of immune escape mechanisms. One of the major pathways involved in the immune escape of cancer cells is the activation of PD-1/PD-L1 pathway.
We have researched how this pathway is activated in lung cancer, and continue to study the dynamic interaction between tumor and immune cells to better understand lung cancer initiation, progression, and response to treatments.
In addition to the cell intrinsic effects, oncogenes and tumors suppressor provide survival advantage to tumor cells by promoting immune evasion. We found a significant correlation between the expression of genes marking the activation of the EGFR pathway and the PD-1/PD-L1 regulatory immune checkpoint pathway in mouse lung tumors.
Despite the initial dramatic response to PD-1 antibody, acquired resistance of tumors has already been observed in both our preclinical models and in patients. We studied the mechanisms of resistance in preclinical and clinical samples.
Through RNA sequencing of sorted T cells from PD-1 ab-resistant mouse lung tumors we have detected significant upregulation of TIM3, LAG3, and PD-1 immune checkpoint receptors. Flow cytometry analysis in clinical samples confirmed significant upregulation of TIM3 in T cells from patients who previously responded to PD-1 antibody (nivolumab) but developed adaptive resistance.
Inactivating mutations in STK11/LKB1 is a frequent event in lung cancer. Genetic ablation of LKB1 in mouse tumors resulted in accumulation of neutrophils with T-cell-suppressive effects, along with a corresponding increase in the expression of T-cell exhaustion markers and tumor-promoting cytokines. The number of tumor-infiltrating lymphocytes was also reduced in LKB1-deficient mouse and human tumors.
Proinflammatory cytokine Interleukin (IL)-17A (IL-17A) is overexpressed in a subset of patients with Kras mutant lung cancer. To characterize the role of IL-17A in Kras mutant lung tumors, we developed a mouse model of chronic inflammation that more closely resembles human Kras mutant lung cancer through expressing IL-17A constitutively in the lung epithelium and then introducing this allele into lox-stop-lox KrasG12D mutant mice. We found that the production of this single cytokine dramatically changed immune cell dynamics in the tumor microenvironment and promoted resistance to PD-1 blockade.