Breaking Cytokine Loops in Lung Adenocarcinoma

New York University School Of Medicine, New York NY

Investigators

Abstract

Project Summary Lung cancer is the leading cause of cancer related deaths worldwide. For advanced lung adenocarcinoma, the major subtype of lung cancer, the standard of care treatment is immune checkpoint blockade which enhances anti-tumor immune responses. Unfortunately, many patients do not respond to the mechanisms for unclear reasons. LKB1 mutations are found in approximately 20% of lung adenocarcinoma cases. Patients with these specific tumor mutations have poor responses to immune checkpoint blockade and overall worse survival. Currently there are no targeted therapies specifically for LKB1 mutant lung adenocarcinoma. Here I propose to use genetically engineered mouse models, which faithfully recapitulate human lung adenocarcinoma, to define how these specific tumors interact with the microenvironment. We have previously shown that LKB1 mutant tumors, through an autocrine LIF signing pathway, promote tumor dedifferentiation and, through expression of an inflammatory signature, recruits immunosuppressive myeloid cells. However, we have not delineated the signaling mechanism in which LIF promotes dedifferentiation. Furthermore, while the role of immunosuppressive myeloid cells impairing CD8 T cells is well characterized, little is known about these myeloid cells signal to the tumor cells themselves. I hypothesize that there are two cytokine signaling loops in LKB1 mutant tumors: one in which autocrine LIF signaling promotes tumor dedifferentiation and an increase in inflammatory markers promoting neutrophil and macrophage recruitment and a second cytokine loop where myeloid cells release Il-1β to amplify the inflammatory signal of LKB1 mutant tumors. In Aim 1 I will use Lkb1 mutant lung cancer mouse models to interrogate the autocrine LIF signaling loop using scRNA-seq and scATAC-seq to identify signaling mediators for tumor dedifferentiation and inflammation. I will then perform CRISPR/Cas9 editing to generate knockouts to validate those findings. In Aim 2 I will initiate Lkb1 mutant lung tumors with knockout of the receptor for IL-1β and measure changes to the immune microenvironment as well as tumor growth. I will then investigate the therapeutic role of IL-1β neutralization in the context of Lkb1 mutant tumors. The proposed study will be led by Dr. Ray Pillai, a Clinical Instructor at NYU Grossman School of Medicine under the co-mentorship of Drs. Thales Papagiannakopoulos and Sergei Koralov who have combined expertise in cancer mouse models, immunology, and metabolism. Both mentors have created a training plan where Dr. Pillai will transition to an independent investigator. An advisory committee, consisting of Drs. Kwok-Kin Wong, Dan Littman, and Mark Philips, will also help guide Dr. Pillai on his path to becoming a physician scientist.