New Modalities

Defining the breadth and specificity of drug response in heterogeneous immune cell populations

Tuesday, January 26, 2021

5:15 PM – 5:40 PM EST

Sponsored By: Beckman Coulter Life Sciences

Human diseases are fundamentally multicellular in nature with many different cell types contributing to disease progression and treatment response. However, how drugs impact each cell type in a heterogeneous population remains poorly understood. Conventional drug response studies, including those using single-cell profiling based approaches, have focused on pure cell types, ignoring population-level effects. Here, we applied highly multiplexed single cell mRNA-seq to study the impact of over 500 immunomodulatory compounds on human primary blood mononuclear cells (PBMCs), a heterogenous mixture of myeloid and lymphoid immune cell-types. We profiled over one million single cells using MULTI-seq to multiplex samples and used PopAlign, a probabilistic modeling platform, to discover cell-type specific responses for each compound in the library. Our conditions include CD3/CD28 stimulation, which activates signaling interactions that unmasks a wide range of drug responses that are not observed in resting cell populations. Our results highlight cell type-specific patterns of response: while many drugs inhibit T-cell activation in a similar manner, drug impact on macrophages are diverse. By classifying cell-type specific drug response signatures across conditions, we could identify two types of immunomodulators: localized and broad regulators of immune activation. We find localized inhibitors that act specifically on macrophages, such as TLR agonists and NSAIDs which induce pro-inflammatory and apoptotic programs, respectively. Broad modulators impact more than one cell-type; they inhibit activation in T cells but can push macrophages into inflammatory (M1), non-inflammatory (monocyte-like), anti-inflammatory (M2) or drug-specific transcriptional states. For instance, while JAK inhibitors and calcineurin inhibitors shift the balance toward non-inflammatory monocytes, some VEGFR and Bcr/ABL inhibitors generate more inflammatory M1 macrophages. Our analysis also reveals novel local activity for previously poorly characterized molecules, including a myeloid-suppressing function of a group of compounds including NSAIDs and an artificial sweetener. By providing new depth and insight into how existing compounds reshape immune populations, our dataset is a promising resource for improving therapeutic strategies, especially in cancer where macrophage state (M1/M2) can advance or reverse disease progression. Our platform can be broadly applied towards understanding heterogeneous cell populations in a wide range of therapeutic and disease conditions.