Lung fibrosis impairs tumor immunity and limits immune checkpoint efficacy

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY/ABSTRACT The long-term goal of this proposal is to train the applicant to become an independent, academic physician- scientist studying immune responses against lung cancer. The principal investigator (PI) has previously obtained Ph.D. training in biochemistry and molecular biology, as well as clinical training in internal medicine and hematology/oncology. He is ABIM board-certified in medical oncology. This application describes a 5- year career development program that will provide the PI a mentored educational experience with the aim of developing new scientific expertise in tumor immunology, molecular profiling, high-dimensional analysis, computational biology, and mouse models of human lung cancer. At the conclusion of the award period, the PI will have acquired the skills necessary to achieve his goal of becoming an independent investigator in an academic medical center studying lung cancer immunobiology and immunotherapy and caring for patients with thoracic malignancies. This research project will capitalize on the expertise and environment of Washington University in St. Louis, which has a long-track record of developing and supporting physician-scientists. Dr. David DeNardo will mentor the PI’s scientific and career development. Dr. DeNardo's work is responsible our critical understanding of how the tumor microenvironment of pancreatic cancer leads to impaired immune surveillance and his work has led to several clinical trials on improving immune-based therapies in pancreatic cancer. An advisory committee of scientists will provide additional scientific and career guidance. Lung cancer is the most common cause of cancer-related mortality worldwide. Immune checkpoint inhibition, though revolutionary, is beneficial for a subset of patients with metastatic non-small cell lung cancer (NSCLC). Unfortunately, the responses are often not durable with nearly 80% of those diagnosed with advanced stage NSCLC succumbing to their disease within 5 years of diagnosis. The tissue microenvironment of human NSCLC is characterized by a dense stromal network. Our laboratory has demonstrated that CAFs can impair response to anti-tumor immunity in pancreatic cancer as well as in models of NSCLC. We have found that targeting fibrosis via TGFbR inhibition can improve responses to immune checkpoint inhibition but only in the setting of chemotherapy. In this proposal, we will test the hypothesis that fibrosis impairs both T-cell priming and antigen trafficking/presentation and these are restored when TGFbR inhibition is combined with chemotherapy and immunotherapy. For these studies, we will utilize a genetically engineered mouse model of human lung adenocarcinoma, the most common type of NSCLC, which expresses ovalbumin, which will enable us to assess immune responses. The identification of the cellular and molecular mechanisms by which TGFbR inhibition restores anti-tumor immunity when combined with chemotherapy and immunotherapy has clinically relevant implications with respect to the development of novel immunotherapy strategies for patients with NSCLC.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE: Immune checkpoint inhibitors, either alone or in combination with cytotoxic chemotherapy, are standard treatments for patients with metastatic lung cancer, yet less than half of patients will experience a reduction in size of their tumors and these responses typically last less than one year. This limited efficacy is in part due to an immunosuppressive fibrotic microenvironment characterized by impaired T cell function as well as dysfunctional antigen presentation. We will identify mechanisms by which TGFb inhibition in combination with chemotherapy can restore anti-tumor immunity to enhance immune checkpoint blockade.