Targeting myeloid cells in the tumor microenvironment

Abstract

Myeloid cells are central regulators of the tumor microenvironment (TME), where they frequently accumulate and drive immunosuppression and disease progression. Through the production of reactive oxygen species (ROS), primarily via the NOX2 enzyme, and inflammatory cytokines such as interleukin-1β (IL-1β), they can suppress cytotoxic lymphocytes, including T cells and natural killer (NK) cells, and contribute to metastasis in solid tumors as well as leukemic cell survival and expansion. However, myeloid cells are functionally plastic and can also exert anti-tumor effects under specific conditions. This thesis investigated strategies to target and reprogram suppressive myeloid cells to restore anti-tumor immunity and limit disease progression across both solid tumors and hematological malignancies. In Paper I, histamine dihydrochloride (HDC) was shown to induce the production of the anti-angiogenic factor thrombospondin-1 (TSP-1) via cAMP/PKA signaling in myeloid cells, contributing to reduced melanoma metastasis. In Paper II, NOX2-dependent ROS-producing myeloid cells were identified as key regulators of NK-cell-mediated control of lung and liver metastasis in pancreatic ductal adenocarcinoma (PDAC), supporting NOX2 inhibition as a potential therapeutic strategy. In Paper III, HDC/IL-2 treatment was associated with reduced IL-1β levels in acute myeloid leukemia (AML) patients in first complete remission, and lower IL-1β levels were associated with improved leukemia-free survival, consistent with a role for inflammatory myeloid cytokines in relapse risk. In Paper IV, Bruton’s tyrosine kinase inhibition blocked NOX2 activation in myeloid cells and enhanced NK-cell-mediated killing of malignant cells under immunosuppressive conditions. Overall, these studies highlight the context-dependent and plastic roles of myeloid cells across cancer types and demonstrate that targeting their suppressive programs while promoting protective functions represents a promising therapeutic strategy.