Chi3l1 Regulation of Checkpoint Regulating, Costimulatory, and Coinhibitory Molecules in Primary and Metastatic Lung Cancer
Abstract
Lung cancer is an urgent and serious health issue among Veterans where its prevalence is higher than in civilian populations and its morbidity and mortality exceed that of all of the other major cancers combined. Until recently, the goal for lung cancer patients was to diagnose the disease early enough to be able to cut it out surgically. Patients in whom the cancer was too advanced to remove frequently received chemotherapy or radiation. However, this rarely improved overall survival. One of the most exciting recent discoveries in cancer is the appreciation that evasion of the host anticancer immune response and suppression of T cell responses are essential for cancer development and progression. Studies of these responses have highlighted essential immune checkpoint inhibitors (ICPI) that inhibit anti-cancer responses. These advances have led to the development of ICPI blocking antibodies, which have proven to be successful short-term therapeutics for lung and other cancers. However, the mechanisms that tumors use to stimulate ICPI have not been defined. Chitinase 3-like-1 (Chi3l1; also called Chitinase like 1 (Chil1) in the mouse and YKL-40 in man) is a protein expressed in an exaggerated fashion in the serum and or tissues from patients with a variety of malignancies including lung cancer. In many of these malignancies, there is a strong correlation between the levels of Chi3l1/YKL-40 and disease progression, a poor prognosis and shorter disease-free survival. However, the exact roles of Chi3l1/YKL-40 in the development and progression of lung cancer have not been determined. To investigate in vivo roles of Chi3l1/YKL-40/Chil1, we generated genetically modified mice that lack this molecule (referred to as Chil1-/-mice) and mice in which this protein is overexpressed in the lung (called YKL-40 Tg mice) and compared the metastatic spread of tumors to the lung and the development and progression of primary lung cancers in these genetically modified mice and in normal control animals. The studies of metastatic spread demonstrated that Chi3l1/Chil1 is induced during these responses, where it plays a critical role in allowing metastatic tumors to develop in the lung. They also demonstrated that interventions that activate a unique immune pathway called the RIG-like helicase pathway inhibit the induction of Chi3l1/Chil1 and abrogate tumor spread. In experiments in which primary cancer was induced in the lungs of the mice, we noted that Chi3l1/Chil1 is induced. In mice that lack Chi3l1/Chil1, the development of tumors was markedly blunted while in mice in which Chi3l1/Chil1 was overexpressed, tumor development was enhanced. When viewed in combination, these studies demonstrate that Chi3l1/YKL-40/Chil1 plays critical roles in the pathogenesis of primary and metastatic lung cancer. However, the mechanism via which Chi3l1/YKL-40/Chil1 mediate these responses have not been defined. To address this issue, studies were undertaken to determine if Chi3l1/YKL-40/Chil1 regulated ICPI or T cell co-stimulators. These studies demonstrated that Chi3l1/YKL-40/Chil1 is a critical stimulator of ICPI and inhibitor of T cell co-stimulators. This led to the hypothesis in this proposal, that Chi3l1/YKL-40 plays a critical role in the pathogenesis of lung cancer by acting as a major stimulator of ICPIs while simultaneously decreasing T cell activation. To address this hypothesis we will: Aim 1: Define the expression and roles of Chi3l1 in the development and progression of primary lung cancer. Aim 2: Characterize the regulation of Chi3l1 induction in lung cancer with a focus on RLH innate immunity. Aim 3: Characterize the roles of Chi3l1 in the induction/regulation of ICPI and T cell co-stimulators in murine primary and metastatic lung cancer. Aim 4: Determine if the levels of circulating or tissue Chi3l1/YKL-40 correlate with patient responses to immune checkpoint-based therapeutic interventions (ICPTI). If succes
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710196
Entities
People
- Jack Elias
Organizations
- Brown University
- United States Army