To improve anti-PD-1/PD-L1 responses in cancer, Kumar, Tailor, and Dheeraj et al. developed an ex vivo, high-throughput screen to identify drugs that could inhibit macrophage-mediated T cell suppression. A total of 1430 FDA-approved small-molecule drugs were screened in a co-culture of bone marrow-derived macrophages and splenic T cells. 57 compounds were identified that blocked macrophage-mediated T cell suppression, and 7 showed synergistic T cell expansion with anti-PD-L1. COX1/2 inhibitors emerged as the top candidates, and when combined with anti-PD-L1, significantly improved OS in TNBC tumor models in a CD8+ T cell-dependent manner.
Contributed by Katherine Turner
ABSTRACT: Tumor-associated macrophages (TAMs) and other myelomonocytic cells are implicated in regulating responsiveness to immunotherapies, including immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis. We have developed an ex vivo high-throughput approach to discover modulators of macrophage-mediated T cell suppression, which can improve clinical outcomes of ICIs. We screened 1,430 Food and Drug Administration (FDA)-approved small-molecule drugs using a co-culture assay employing bone-marrow-derived macrophages (BMDMs) and splenic-derived T cells. This identified 57 compounds that disrupted macrophage-mediated T cell suppression. Seven compounds exerted prominent synergistic T cell expansion activity when combined with _PD-L1. These include four COX1/2 inhibitors and two myeloid cell signaling inhibitors. We demonstrate that the use of cyclooxygenase (COX)1/2 inhibitors in combination with _PD-L1 decreases tumor growth kinetics and enhances overall survival in triple-negative breast cancer (TNBC) tumor models in a CD8(+) T cell-dependent manner. Altogether, we present a rationalized approach for identifying compounds that synergize with ICI to potentially enhance therapeutic outcomes for patients with solid tumors.
Author Info: (1) Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA. (2) Department of Cell, Developmental & Cancer Biology, Oregon Health
Author Info: (1) Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA. (2) Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA; Center for Experimental Therapeutics, Oregon Health & Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. (3) Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA; Center for Experimental Therapeutics, Oregon Health & Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. (4) Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA; Center for Experimental Therapeutics, Oregon Health & Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. (5) Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA; Center for Experimental Therapeutics, Oregon Health & Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. (6) Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA; Center for Experimental Therapeutics, Oregon Health & Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. (7) Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR, USA. (8) Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR, USA. (9) Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. (10) Center for Experimental Therapeutics, Oregon Health & Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Division of Hematology & Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR, USA. (11) Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. Electronic address: coussenl@ohsu.edu. (12) Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA; Center for Experimental Therapeutics, Oregon Health & Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. Electronic address: malhotsa@ohsu.edu.
