LonP1 Inhibition: A Novel Approach to Tackle Tumor-Associated Macrophages
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Mentor Information
Dr. Paulo Rodriguez, Dr. Rachel Jimenez
Description
Immunotherapy is a groundbreaking approach in oncology. Yet, immunotherapy can be hindered by immunosuppressive cells such as tumor-associated macrophages (TAMs). LonP1 is essential in the mitochondrial stress response and is overexpressed in tumors and by TAMs. Therefore, tumor expression of LonP1 represents a promising target to improve immunotherapy efficacy. To assess tumor growth inhibition by targeting LonP1, mice received B16F10 melanoma cells subcutaneously, followed by alternate-day intraperitoneal injections of a small molecule LonP1 inhibitor (LonP1i) or PBS control. At endpoint, tumor-infiltrating myeloid cells and T cells were analyzed via flow cytometry. To test the effect of LonP1i directly on macrophages, bone marrow- derived macrophages were treated with Lonp1i or PBS control, co-cultured with antigen-specific T cells and analyzed by flow cytometry. LonP1i-treated mice showed markedly slower tumor growth than PBS-treated groups. Flow cytometry revealed higher counts of total macrophages and neutrophils in LonP1i-treated versus PBS-treated groups. In LonP1i-treated tumors, a significant increase in the subset of Ly6C+MHC-II- recently infiltrated macrophages were observed compared to the PBS-treated tumors. In the in-vitro study, LonP1i-treated macrophages stimulated greater proliferation of T cells compared to the PBS-treated macrophages. This suggests a potential role for LonP1 inhibition to enhance macrophage-driven T cell proliferation and activation within the tumor microenvironment. LonP1 inhibition demonstrated significant reduction in tumor growth and altering the composition of the tumor microenvironment, particularly through the expansion of macrophage populations. These findings underscore the potential of LonP1 inhibition as a promising strategy that can be combined with immunotherapy to minimize the immunosuppression from TAMs.
LonP1 Inhibition: A Novel Approach to Tackle Tumor-Associated Macrophages
Immunotherapy is a groundbreaking approach in oncology. Yet, immunotherapy can be hindered by immunosuppressive cells such as tumor-associated macrophages (TAMs). LonP1 is essential in the mitochondrial stress response and is overexpressed in tumors and by TAMs. Therefore, tumor expression of LonP1 represents a promising target to improve immunotherapy efficacy. To assess tumor growth inhibition by targeting LonP1, mice received B16F10 melanoma cells subcutaneously, followed by alternate-day intraperitoneal injections of a small molecule LonP1 inhibitor (LonP1i) or PBS control. At endpoint, tumor-infiltrating myeloid cells and T cells were analyzed via flow cytometry. To test the effect of LonP1i directly on macrophages, bone marrow- derived macrophages were treated with Lonp1i or PBS control, co-cultured with antigen-specific T cells and analyzed by flow cytometry. LonP1i-treated mice showed markedly slower tumor growth than PBS-treated groups. Flow cytometry revealed higher counts of total macrophages and neutrophils in LonP1i-treated versus PBS-treated groups. In LonP1i-treated tumors, a significant increase in the subset of Ly6C+MHC-II- recently infiltrated macrophages were observed compared to the PBS-treated tumors. In the in-vitro study, LonP1i-treated macrophages stimulated greater proliferation of T cells compared to the PBS-treated macrophages. This suggests a potential role for LonP1 inhibition to enhance macrophage-driven T cell proliferation and activation within the tumor microenvironment. LonP1 inhibition demonstrated significant reduction in tumor growth and altering the composition of the tumor microenvironment, particularly through the expansion of macrophage populations. These findings underscore the potential of LonP1 inhibition as a promising strategy that can be combined with immunotherapy to minimize the immunosuppression from TAMs.
