Targeting Tinagl1 to Enhance Immunotherapy Response in Lung Cancer
Abstract
Lung cancer is the leading cause of cancer-related death and accounts for more than 20% of all cancer deaths. Non-small cell lung cancer (NSCLC), which consists of 80-85% of lung cancers, is one of the most devastating diseases that threaten our health. Recently, immune checkpoint inhibitor (ICI) therapy, such as anti-PD-1/PD- L1, which boosts our own cytolytic immune cells (e.g., CD8+ T cells) to enhance immune surveillance to against tumor cells, has revolutionized lung cancer treatment. Unfortunately, the vast majority of NSCLC patients do not response to this attractive therapy. It is urgent to identify an effective biomarker to precisely identify the NSCLC patients who could benefit from ICI therapy. More importantly, it is imperative to uncover the mechanisms through which NSCLC patients develop ICI treatment resistance. Previous study indicated that Tubulointerstitial nephritis antigen-like 1 (Tinagl1) is involved in cancer progression; however, its oncological function in lung cancer is largely unknown. Our preliminary analysis with publicly available datasets suggests that Tinagl1 is correlated with worse clinical outcomes in NSCLC patients. Moreover, Tinagl1 expression is negatively correlated with CD8 expression in patient tumor samples, and NSCLC patients who response to ICI therapy have lower Tinagl1 expression levels. These results suggest that Tinagl1 may serve as a biomarker to predict the ICI treatment response in NSCLC patients. In addition to these correlation studies, our mouse model-based in vivo experiments revealed that Tinag1 inhibits CD8+ T cell infiltration into the lung tumors, and therefore, enhances immune evasion to promote NSCLC progression. Mechanistically, Tinagl1 inhibits tumor antigen processing and presentation to help tumor cells to escape from CD8+ T cell s recognition and killing. Encouraged by these promising preliminary data, in this proposed study, we aim to uncover the mechanism underlying Tinagl1-mediated tumor antigen presentation-suppression and the consequent immune evasion and lung cancer promoting. Given the functional importance of Tinagl1 in lung cancer promoting, we speculate that targeting this gene may have therapeutic potential. In this regard, we have developed Tinagl1 antisense oligonucleotides (ASOs). These Tinagl1-ASOs exhibited remarkable tolerability in our mouse models and can effectively knockdown endogenous Tinagl1 in vivo. Next, we will evaluate the therapeutic potential of these Tinagl1-ASOs. Considering that Tinagl1 induces immune evasion to promote NSCLC progression, we will test if Tinagl1-ASOs treatment restores tumor immune surveillance, and more importantly, we will investigate whether Tinagl1-ASOs sensitize NSCLC to CD8+ T cell-targeted therapy, such as anti-PD-1. The outcomes of this proposed study will address the following three areas of emphasis: (1) understand the molecular mechanisms of initiation and progression to lung cancer; (2) identify innovative strategies for treatment of lung cancer; and (3) develop or optimize biomarkers to assist with therapeutic decision-making. In addition to the exciting preliminary results we have obtained and the in vivo lung cancer mouse models we have generated, this study is also supported by an interdisciplinary team of scientists from both preclinical and clinical filed with extensive lung cancer research experience. Moreover, the proposed study is fully supported by our state-of-the-art facilities, such as an animal facility, which is essential for us to evaluate the therapeutic potential of Tinagl1-ASOs in mouse models, as well as the Biobanking and Correlative Sciences Core, which will enable us to validate our findings in NSCLC patient samples. With these collaboration and support, we are confident in our ability to successfully carry out the proposed research project. We believe that the proposed project will provide insight into the mechanisms underlying immune evasion during
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310297
Entities
People
- Minhong Shen
Organizations
- United States Army
- Wayne State University