Project 3: Targeting Vulnerabilities in the Fibrotic Extracellular Matrix (ECM) of Lung Cancers

项目摘要/摘要

Project 3 Project Summary/Abstract Substantial therapeutic advances have been made in the treatment of non-small cell lung cancer (NSCLC) based on the incorporation of immune checkpoint inhibitors of the PD-1/PD-L1 axis. Unfortunately, the majority of patients do not benefit from this single-agent approach, either due to primary or acquired resistance mechanisms. There is a knowledge gap about the interplay between the tumor-infiltrating immune cells and the dynamic changes in the extracellular matrix and tumor microenvironment that may drive an immunosuppressive microenvironment, which translates into a major unmet therapeutic need. The members of our multidisciplinary team (Gibbons, Kurie, Cascone, Yamauchi, Dalby, Wistuba, and Wang) have a track record of productivity in studying tumor matrix dynamics and immune factors in the microenvironment during lung cancer progression and in response to immune therapy. The investigators bring expertise in mouse modeling of human lung cancer, clinical oncology, immunotherapy, molecular pathology of lung cancer, drug development and bioinformatics/biostatistics. We have developed preliminary data from analysis of human lung cancer specimens and preclinical genetically engineered mouse models (GEMMs) of NSCLC that the deposition and crosslinking of the collagen matrix suppresses intratumoral surveillance by immune cells. Based on these findings, we hypothesize that extracellular matrix deposition and collagen crosslinking in the tumor microenvironment suppress tumor-infiltrating immune cells, facilitating tumor invasion and metastasis. Through parallel study of pre-clinical models and assessment of patient samples, we will address this hypothesis and explore clinical translational opportunities by: 1. evaluating the role of collagen crosslinking enzymes and a fibrotic extracellular matrix on the immune cell profile of murine and human lung tumors; 2. determining how treatment with immune checkpoint inhibitors (ICI, e.g. anti-PD-(L)1 and/or anti-CTLA-4) alters extracellular matrix composition and crosslinking in murine and patient tumors; and 3. testing the efficacy of agents that block fibrotic collagen crosslinking or collagen-mediated T cell suppression, with or without immune checkpoint inhibitors to reverse the suppression of a productive intratumoral immune response in preclinical models. The Human Endpoint is demonstrated in our analysis of key ECM features in: A. SPORE tumor samples; B. 150 paired surgical tumor/normal samples and >500 blood samples from previously untreated patients with stage IB-IIIA NSCLC from the MDACC ImmunogenomiC prOfiling of NSCLC (ICON) study; C. 44 paired tumor/normal samples from patients treated on the MDACC NEOSTAR study of neoadjuvant ICI for resectable stage I-IIIA NSCLC; and D. tumors from patients after treatment with the multi-kinase inhibitor nintedanib.