Analysis and Targeting of Tumor-Associated Monocytes/Macrophages that Inhibit PD-1 Blockade
Margaret Shipp
MDDana-Farber Cancer Institute
Project Term: June 30, 2023 - June 30, 2026
Inhibition of a tumor-triggered immune exhaustion pathway, termed PD-1 blockade, enables immune effector cells to attack cancers. In classic Hodgkin Lymphoma (cHL), PD-1 blockade is now a standard treatment for relapsed disease and a component of experimental frontline therapy. We have identified a major population of monocyte/macrophages in patients with cHL that inhibit tumor cell killing and limit the efficacy of PD-1 blockade. Our goal is to fully characterize these tumor-specific monocytes/macrophages and target their immunosuppressive and tumorigenic program for therapeutic benefit in patients with cHL and other lymphoid malignancies.
Immunotherapy has transformed the treatment of certain lymphoid malignancies, including classical Hodgkin lymphoma (cHL) and related disorders. Inhibition of a tumor-triggered immune exhaustion pathway, termed PD-1 blockade, enables immune effector cells to attack cancers. In cHL, PD-1 blockade is now a standard treatment for relapsed disease and a component of experimental frontline therapy for newly diagnosed tumors. For these reasons, it is essential to identify and characterize mechanisms of resistance to PD-1 blockade that represent promising new treatment targets.
We analyzed the circulating single-cell immune signatures in patients with cHL at diagnosis and relapse, before and during PD-1 blockade, and compared these findings to those in healthy donors. Patients with cHL had dramatically increased numbers of a novel monocyte/macrophage subtype that was not found in healthy donors. Depending upon their programming, monocytes/macrophages can either promote tumor cell killing or inhibit an anti-tumor immune response. Our preliminary data suggest that the newly identified monocyte/macrophages in patients with cHL produce multiple soluble factors and express cell surface proteins that function in concert to inhibit tumor cell killing and limit the efficacy of PD-1 blockade. We have identified similarly programmed monocyte/macrophages that inhibit PD-1 blockade in the immediate proximity of malignant Hodgkin Reed Sternberg cells in primary tumors. Initial analyses of the RNA signatures of these tumor-programed monocytes/macrophages identify disease-defining regulatory pathways, promising treatment targets and candidate inhibitors that are already available for clinical trials. The overall goal of this proposal is to fully characterize these tumor-specific monocytes/macrophages and target their immunosuppressive and tumorigenic program for therapeutic benefit in patients with cHL and other lymphoid malignancies.