Defective Tumor Mitochondria Drives Intrinsic Immunogenicity Through MHC Class 1 Antigen Presentation and T-Cell Engagement
Abstract
The Challenge Statement of this Fiscal Year 2021 (FY21) Melanoma Research Program (MRP) Idea Award entitled Defective tumor mitochondria drives intrinsic immunogenicity through MHC class 1 antigen presentation and T cell engagement responds to a new paradigm of prevention impeding the progression of primary melanoma and blocking development of micro-metastases. This application falls under the FY21 MRP Focus Area because the outcomes will provide innovative information on how the tumor immune microenvironment impact tumor initiation, response to therapy, progression, and dormancy. Ideas and Reasoning Behind the Proposed Work. Immunotherapy with immune checkpoint inhibitors have provided a significant advance to treat melanoma patients; however, a large percentage of these patients fail to respond to this therapy. Thus, alternative ways to trigger immune (our defense system) attack to kill melanomas would constitute a significant advance. We have found that one of these alternative ways is to selectively block melanoma mitochondrial (powerhouse of the cell) energetics. The idea in this application is to block melanoma mitochondrial energetics to trigger an immune attack against these cancer cells. Ultimate Reason for the Research. To use specific drugs that selectively and partially inhibit mitochondrial bioenergetics in tumor cells that will initiate an immune attack to kill melanoma cells. How the Research Introduces a Novel Concept. The novel concept is to specifically target the bioenergetic center of the cancer cell, causing immune cells to kill and eliminate tumors. This bioenergetic center can be targeted using genetic tools or specific drugs. The interference with the bioenergetics generates signals, including formation of new antigens (targets of the immune T cells), that will attract immune cells infiltrating and destroying the melanoma. How the research will lead to new avenues to discover, develop, or create new avenues in the prevention of melanoma initiation and progression. This research is divided in three blocks, (1) studies using instrumentation and machines to discover melanoma proteins that cause the immune attack; (2) studies using the same machines to discover antigens that cause attraction and infiltration of immune cells into the melanoma. This infiltration will kill and destroy the tumor; (3) laboratory experiments using melanoma mouse models to test the proteins that are necessary and trigger the immune attack. The discovery and results in these three blocks will lead to new avenues and ways to prevent melanoma initiation and progression. These new avenues will be centered on (1) drugs that target the bioenergetic center, and (2) drugs that target the proteins that interfere with the discovered proteins that are necessary for the immune attack. These drugs, either existing or generated through future drug development programs could be used either alone or with combination of already clinically approved therapies such as BRAF and MEK inhibitors or immune checkpoint inhibitors. What Types of Patients Will the Research Help and How Will It Help Them? This research will specifically help melanoma patients who do not respond to immune checkpoint inhibitors, because they might generate an additional immune response that will destroy the melanomas. What Are the Potential Clinical Applications, Benefits, and Risks? The potential clinical applications are the possibility of use of additional drugs, targeting the bioenergetic center or proteins interfering the immune response, that through the immune T cells will kill the melanoma. Potential risks, although safety has been observed in preliminary studies, could be the drugs might target some non-malignant cells, or they might trigger an overall strong immune response. These risks will be evaluated in future studies. Describe the Long-Term Impact on Patient Outcomes. The potential use of the drugs and ways to trigge
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210780
Entities
People
- Pere Puigserver i Burguera
Organizations
- Dana–Farber Cancer Institute
- United States Army