Dana-Farber Cancer Institute
Project Term: July 1, 2023 - June 30, 2026
Inhibition of the PD-1 exhaustion pathway enables the immune system to attack cancers. PD-1 blockade is now a standard treatment for relapsed classic Hodgkin Lymphoma (cHL) and a component of experimental frontline therapy. In patients with cHL, a newly identified population of monocytes/macrophages limits the efficacy of PD-1 blockade. We will characterize and target these tumor-programmed monocytes/macrophages 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 the related disorder, primary mediastinal B-cell lymphoma (PMBL). The PD-1 exhaustion pathway limits the efficacy of an anti-tumor immune response in both in cHL and PMBL. PD-1 blockade enables immune effector cells to attack the malignant cells in both lymphoid malignancies. In cHL and PMBL, PD-1 blockade is now a standard treatment for relapsed disease and a component of experimental frontline therapy for newly diagnosed tumors. However, the rate of complete response and durable complete remission to single agent PD-1 blockade is still low in cHL and PMBL. 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 at 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 suggests that the newly identified monocyte/macrophages in patients with cHL produce multiple soluble factors and express cell surface proteins that inhibit tumor cell killing and limit the efficacy of PD-1 blockade. We have identified similarly programmed monocyte/macrophages that inhibit the efficacy of PD-1 blockade in the immediate proximity of malignant cells in primary tumors.
Initial analyses of the RNA signatures of these tumor-programed monocytes/macrophages identify disease-defining regulatory pathways and promising treatment targets. Of importance, candidate inhibitors of prioritized targets are already available for evaluation in clinical trials. The overall goal of this fellowship proposal is to fully characterize the newly identified tumor-specific monocytes/macrophages and target their immunosuppressive and tumorigenic program for therapeutic benefit in patients with cHL and other lymphoid malignancies.