Metabolic Reprogramming of the Immunosuppressive Myeloid Niche in Soft Tissue Sarcoma as a Means of Enhancing Immunotherapy
Abstract
Relevance to Military Health: This proposal focuses on the Fiscal Year 2021 Peer Reviewed Cancer Research Program Topic Area of Sarcoma. Sarcomas are very important diseases for the military health system (MHS) to study because of the potential etiology of military-related exposures, the life- and limb-threatening nature of these diseases, the cost to the MHS, and the special surgical training that sarcoma cases provide for military graduate medical education. Soft tissue sarcomas (STS) are a group of cancers that start in the soft tissue, which are the tissues that connect, support, and surround other body structures. An example are the soft tissues (tendons, ligaments, muscle) around the knee joint. There are currently more than 50 different types of STS. It is common for STS to occur in the arms and legs and even in the abdominal cavity. There are often no symptoms in early stages. The first noticeable symptom is usually a painless lump or swelling. As the tumor grows, it may cause other symptoms, such as pain or soreness. Typically, surgery is the most common way to treat these cancers, and it can be quite effective when the sarcoma is diagnosed early and localized. However, other cancer treatment options such as chemotherapy and radiation therapy may be used depending on the size, location, degree of spread, and type of soft tissue cancer. Unfortunately, treatment outcomes for STS that have spread throughout the body have not improved in decades; the majority of these patients die of their underlying disease despite undergoing months of intensive chemotherapy and disfiguring surgery. Cancer cells aim to weaken or disarm the otherwise powerful human immune system. The longer cancer cells face a weakened immune response, the more they are able to adapt and grow, and the easier it is for them to manipulate immune cells within the tumor’s location. The space within the tumor mass is referred to as the tumor microenvironment or tumor microenvironment (TME). The TME is a dynamic battlefield, pitting recruited immune cells against rapidly dividing, malignant cells. Immunotherapy harnesses the power of the immune system by helping it recognize cancer cells that have been multiplying and targeting them for destruction. It uses the body’s natural immune system to target cancer cells exclusively, leaving healthy cells alone, thereby limiting innocent bystander casualties. The immune system is smart and adaptable just like cancer, so it can learn to recognize cancer cells and attack them. It also has the ability to remember specific cancer cells so they can be found and targeted in the future if the cancer returns, which may provide a long-lasting response to treatment. Current immunotherapy approaches haven’t had a great deal of success in killing the sarcoma tumor cells, and the reasons why are largely unknown. Through our research across multiple types of STS, we have discovered the presence of highly immunosuppressive types of cells called tumor infiltrating myeloid cells (TIMs) in the majority of sarcomas. These cells have been shown to suppress the good cells of the immune system, which are recruited to kill the tumor cells. Thus, TIMs trick the immune system into slowing down, and this allows the cancer to take control of the process the body uses to regulate the immune response. We believe TIMs are a major reason why immunotherapies are not leading to positive outcomes in patients with STS. In this proposal, we aim to identify the attractive forces leading these TIMs to converge and dominate the tumor microenvironment and the mechanisms they utilize to suppress the immune cells whose job is to kill the cancer cells. Secondly, we will try to dismantle these immunosuppressive functions of these cells by putting a stick in their metabolic cycles and forcing them to become one of the good guys. We will do so by blocking their glutamine supply using a novel drug that is currently in clinical trial
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210548
Entities
People
- Nicolas Llosa
Organizations
- Johns Hopkins University
- United States Army