Targeting Tumor-Intrinsic Immunosuppressive Mechanisms to Enhance Efficacy of Immune Checkpoint Blockade in Lung Cancer
Abstract
Of the 1.8 million individuals diagnosed with lung cancer per year worldwide, approximately 1.6 million succumb to death. Lung cancer patients with mutation in the KRAS oncogene have the worst prognosis, as they respond poorly to standard chemotherapeutic regimens compared with the general non-small-cell lung cancer (NSCLC) population. Despite this clinical significance, there is not a single effective Food and Drug Administration-approved targeted therapy against mutant KRAS lung cancer. Given the unmet clinical demand, there is an urgent medical need to develop targeted therapeutic approaches for effective treatment of mutant KRAS NSCLC. In an effort to identify a novel and more effective targeted therapy, we have focused on the endoplasmic reticulum (ER) stress response that develops in progressing tumors. Adverse conditions in the tumor milieu, such as hypoxia, nutrient starvation, low pH, and free radicals, rapidly disrupt the protein-folding capacity of the ER, thereby triggering a state of cellular “ER stress.” Cancer cells adapt to such adverse conditions by adjusting their protein-folding capacity via activation of the IRE1a-XBP1s arm of the ER stress response. However, the IRE1a-XBP1s signaling pathway has remained relatively unexplored in lung cancer. Recently, we have made the exciting discovery that overactive IRE1a-XBP1 signaling in tumor cells generates a conspicuous immunosuppressive microenvironment in lung cancer. This discovery has led us to believe that the IRE1a-XBP1 pathway is the “Achilles heel” of the disease and constitutes an attractive target for the development of anti-cancer immunotherapy. This proposal aims to dissect the mechanisms by which cancer cell-specific IRE1a-XBP1 signaling generates an immunosuppressive microenvironment that promotes tumor progression by inactivating cytotoxic T lymphocytes and simultaneously increasing immunosuppressive Tregs and MDSCs. Overcoming immunosuppression in the tumor microenvironment is a fundamental prerequisite for the success of clinically relevant immune checkpoint inhibitors, including anti-PD-1 and CTLA4. We posit that treatment with IRE1a selective small molecule inhibitors will overcome major immunosuppressive barriers and boost anti-tumor immunity in NSCLC, which in turn may constitute a new approach in enhancing the efficacy of immune checkpoint inhibitors in NSCLC. This approach has the potential to increase the current objective response rates 17-20% with immune checkpoint inhibitors in NSCLC. We expect that the mechanistic insights from these investigations will generate unique translational opportunities that may lead to the design of future clinical trials for currently untreatable mutant KRAS patients. This project addresses the Lung Cancer Research Program Overarching Challenge of understanding the molecular mechanisms of initiation and progression to clinically significant lung cancer and has the potential to identify innovative strategies for prevention and treatment of lung cancer. It also addresses novel treatment regimens by replacing interventions that have life-threatening toxicities with ones that are molecularly targeted, safe, and effective. Lung cancer is highly prevalent in both Veterans and active-duty personnel due to exposures to mutagens in industrial substances, cigarette smoke, asbestos bearing materials, and battlefield air pollution. The cost of lung cancer to the VA has been suggested to be > $1 billion a year. This study will mechanistically dissect the IRE1a-XBP1 axis that constitutes a major immunosuppressive barrier that limits the efficacy of checkpoint blockade in NSCLC. Targeting the IRE1a has the immense potential to enhance the efficacy of PD-1 inhibition so that a larger cohort of NSCLC patients benefit.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910286
Entities
People
- Vivek Mittal
Organizations
- United States Army
- Weill Cornell Medicine