Targeting Retinoic Acid Signaling for Immunotherapy in Hepatocellular Carcinoma
Abstract
Background: In the United States, nearly 33,000 people are diagnosed with liver cancer and 27,000 die from this disease each year. Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the third leading cause of cancer-related death worldwide. Like most cancer, survival depends on how far the disease has progressed (stage) at the time of diagnosis. If detected early in otherwise healthy patients, surgical resection or liver transplant can be effective. Unfortunately, only a small number of patients are diagnosed at an early stage. Once the disease has spread (metastasized), treatment options are limited and the prognosis is very poor. Overall, the 5-year survival drops from about 32% in “early stage” to less than 2% in metastatic HCC. Given the dismal prognosis, immune checkpoint blockade (ICB) therapy was recently approved for advanced metastatic HCC. However, ICB is not as effective in HCC as in some other types of tumors, and the majority of patients do not respond. Different tumors interact differently with the immune system and therefore may require distinct immunotherapeutic strategy. While the majority of current modalities in cancer immunotherapy act on T cells, our laboratory is interested in targeting another key cell-type of the immune system – antigen-presenting cells. We have discovered that many solid tumors produce retinoic acid, which acts on antigen-presenting cells to create an immune-suppressive tumor microenvironment. Importantly, we showed that blocking retinoic acid in such tumors leads to anti-tumor immune responses. Hence, retinoic acid represents a new target for cancer immunotherapy. Retinoic acid (RA) is a metabolic product of the vitamin-A derivative retinol. We have recently found that HCC produces large amounts of retinoic acid by over-expressing an enzyme known as “RALDH1.” Importantly, our collaborators at the National Institutes of Health (NIH) have developed specific chemical inhibitors of this enzyme. Hence, RALDH1-inhbitiors can potentially reduce retinoic acid levels in HCC to stimulate anti-tumor immune responses, which represents a novel approach in cancer immunotherapy. This is the basic premise of the proposed research. Objective and Rationale: The primary objective of this project is to determine whether targeting retinoic acid signaling is effective for HCC immunotherapy. Toward this goal, we will first examine whether RALDH1 inhibition with our novel compounds can reduce retinoic acid levels in HCC to promote anti-tumor immune responses and then test whether this approach alone or in combination with ICB can restrain HCC growth. We will test our hypothesis using human and mouse HCC cell lines as well as mouse models. Our analytical methods comprise of cutting edge orthogonal approaches, including RNASeq, high dimensional flow cytometry, and T cell clonality assays. Impact and Clinical Applicability: The overarching goal of this project is to generate “proof of concept” for targeting retinoic acid signaling in HCC immunotherapy. If the results are encouraging, we anticipate that our data will form the basis of clinical trials in 1 to 2 years. This proposal is highly innovative, as it builds on our recent discoveries regarding retinoic acid signaling in tumor-immunity, development of first-in-class RALDH1 inhibitors by our collaborators, and its potential to alter the treatment landscape of HCC. Relevance to Military: This proposal addresses two of the Fiscal Year 2020 Peer Reviewed Cancer Research Program Topic Areas: (1) immunotherapy and (2) liver cancer. It also addresses mission readiness, as it has relevance to treatment, quality of life, and survivorship of military member, Veterans, and their beneficiaries.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110592
Entities
People
- Malay Haldar
Organizations
- United States Army
- University of Pennsylvania