Reprograming Osteosarcoma Immune Landscape by STING and Lymphotoxin Receptor Agonists
Abstract
Fiscal Year (FY21) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas: Pediatric, adolescent, and young adult cancers; Sarcoma; Metastatic cancers. In this research project, we propose to examine an idea of a novel strategy to enhance patients’ immune response to osteosarcoma and effectively sensitize the tumor to immunotherapies. There is currently no effective treatment option for chemotherapy-resistant metastatic osteosarcoma, and the survival rate of these patients has not improved for the past 30 years. Although immune checkpoint inhibition therapies have shown impressive efficacy in melanoma, lung cancer, and various other adult cancers, these therapies have shown limited efficacy in osteosarcoma. The success of immune checkpoint inhibition therapies depends on patient’s own immune cells, which fight against cancer cells and kills them. In particular, effector lymphocytes such as T cells and B cells are primarily responsible for anti-tumor immune activity and have a potential to eradicate cancer cells. However, cancer cells often create a type of environment around themselves that inhibits these immune cells from penetrating into the tumor interior. This appears to be particularly problematic in osteosarcoma. On the other hand, immune-reactive tumors are known to contain multiple tertiary lymphoid structures (TLS), which are lymph node-like dense aggregates of T cells, B cells, and other immune cell types. Clinical studies have shown that the presence of TLS within tumors predicts successful outcome of checkpoint immunotherapy in melanoma and sarcoma. Importantly, we found these lymphoid structures in a subset of osteosarcoma, suggesting that some osteosarcoma patients may be responsive to immune checkpoint inhibition therapy. This observation also raised a question how we can promote the development of such immune environment in the remaining, majority of osteosarcoma patients. In this proposal, we explore a potential solution to this question. Recently, we discovered that the combination treatment with agonists of stimulator of interferon genes (STING) and lymphotoxin beta receptor induces an immune-stimulatory tumor environment exhibiting TLS-like dense clusters of lymphocytes. This therapeutic effect has not been previously achieved by existing treatment strategies. We think that this finding offers potential breakthrough for significantly improving osteosarcoma patients’ survival and response rate to T cell-based immunotherapies. FY21 PRCRP Overarching Challenges: Transform cancer treatment through the identification of novel biomarkers and new targets to improve immunotherapy This study will directly examine the importance of immune stimulatory tumor environment for controlling osteosarcoma progression, metastasis, and response to immunotherapies. The proposed study is timely, because several STING agonists have been developed to be tested for various cancer types as single agents or in combination with anti-PD-1 immunotherapy or conventional chemotherapy, and currently, multiple clinical trials are taking place in the U.S. However, STING agonists do not produce the kind of immune environment that is known to be necessary for a significant patient’s response to the immunotherapy. We propose that we can overcome this problem by simultaneously targeting both STING and lymphotoxin receptor. The outcome of this study will be evaluated by medical doctors for the clinical relevance and applicability. For this reason, two sarcoma oncologists are onboard in our research team. Given the translational potential of the project, we anticipate that the successful outcome of this study will have an immediate impact on the cancer research field. Military Health Focus Areas: Mission readiness (Gaps in cancer prognosis, treatment, and survivorship) In the recent advent of immunotherapy, targeting TLS may offer an exciting new opportunity to explore. Osteosarcoma develops mostly
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211051
Entities
People
- Masanobu Komatsu
Organizations
- Johns Hopkins University
- United States Army