Noncanonical Autophagy in Immune Cells as a New Target for Immunotherapy
Abstract
Cancer treatment was revolutionized when scientists discovered how to activate a patients’ own immune system to fight a tumor. Inhibiting the restraints on killer T cells with immune checkpoint inhibitors has resulted in improved treatment for many cancer patients. Unfortunately, some patients have tumors that are seemingly invisible to the immune system, and even responsive tumors are not always eliminated. We have been investigating the autophagy pathway, a process in which material within the cell or outside the cell is encapsulated and degraded. We found that inactivating the autophagy pathway in the immune cells of a mouse results in a more active anti-tumor immune response and reduced melanoma growth. We further found that inactivating autophagy in the cells that surround a tumor can combine with immune checkpoint inhibitors to further reduce melanoma growth to a greater extent than either treatment alone. Autophagy that eliminates cytoplasmic material is important for the viability of immune cells. In contrast, autophagy that degrades phagocytosed material isn’t needed for the health of the immune cells, but does reduce the activation of an immune response. We propose to test whether eliminating only autophagy-mediated phagocytosis in innate immune cells, while retaining cytoplasmic autophagy, will result in an enhanced anti-tumor immune response, including for tumors that would otherwise be missed by the immune system. We will test whether eliminating autophagy-mediated phagocytosis in immune cells can combine with immune checkpoint inhibitors to dramatically reduce melanoma growth. We will also test whether introducing immune cells that have been engineered to eliminate autophagy- mediated phagocytosis into mice with melanomas will heighten their antitumor response and reduce melanoma growth. We will compare the effects of introducing macrophages lacking autophagy-mediated phagocytosis, which will secrete immune system-activating cytokines when they phagocytose dying tumor cells, dendritic cells, which are particularly important for presenting tumor antigens that activate T cells, or both. We anticipate that our findings will represent the intellectual foundation for treatment strategies in which we isolate stem cells from a melanoma patient’s blood, genetically engineer the cells in culture to eliminate autophagy-mediated phagocytosis, induce the stem cells to become innate immune cells, and then re-introduce the engineered cells into patients. We expect that this approach would be widely beneficial for melanoma patients. Some patients with melanoma have immunologically cold tumors. This may correlate with the extent of UV exposure, but involves other factors as well, such as the efficiency of T cell recruitment and activation. Even for patients with hot tumors, immune checkpoint inhibitors may not achieve a complete response. Strategies to increase the effectiveness of immunotherapy could benefit a large fraction of melanoma patients with both cold and hot tumors. The strategy that we propose has multiple advantages. We offer a new approach to cancer treatment vaccines by eliminating autophagy-mediated phagocytosis to increase the immunological potency of introduced immune cells. Eliminating only autophagy-mediated phagocytosis rather than all autophagy is expected to retain the viability of the immune cells. Specifically engineering macrophages and dendritic cells rather than treating the patient systemically with an autophagy-inhibiting drug will preserve the health of the T cells required to mediate the immune response and reduce side effects from loss of autophagy in other tissues. By manipulating the immune cells of a patient and re-introducing the patient’s own cells, the likelihood of rejection is low. Because stem cells can be mobilized and collected from the blood, the patient would only require a blood draw to collect the cells. Finally, the engineered cells
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210920
Entities
People
- Hilary Coller
Organizations
- United States Army
- University of California, Los Angeles