Mendelian randomization of immune cell phenotypes to discover potential drug targets for B-cell malignancy

Abstract

Although treatment options for B-cell malignancies have expanded, many patients continue to face limited response rates, highlighting an urgent need for new therapeutic targets. To prioritize candidate drug targets for B-cell malignancies, we employed Mendelian Randomization to estimate potentially causal relationships between 445 immune cell traits and six B-cell cancers: follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM), totaling 22,922 cases and 394,204 controls. 163 traits showed a suggestive association with at least one B-cell malignancy (P < 0.05), with 34 traits being significant after correction for multiple testing (P < 2 × 10^-4). By integrating findings with observational data and clinical trial evidence to support drug target candidacy, 24 cell surface markers were identified as druggable targets. In addition to established therapeutic targets such as CD3, CD20 and CD38, our analysis highlights BAFF-R and CD39 in HL, CD25 in MM, CD27 in CLL, CD80/86 in DLBCL, and CCR2 in FL and MZL as promising candidates for therapeutic inhibition. Our findings provide further support for the potential of human genetics to guide the identification of drug targets and address a productivity-limiting step.

Fig. 1. Study overview.

Top panel: Overview of genome-wide association studies (GWAS) datasets used in the Mendelian randomization (MR) analysis. The outcome dataset comprised GWAS of six B-cell malignancies and the exposure dataset comprised one GWAS for immune cell traits. Case numbers and relevant publications are provided. Middle panel: Overview of MR, which relies on three key assumptions: (1) IVs must be independent of confounders, (2) associated with the exposure, and (3) influence the outcome solely through the exposure. Bottom panel: Downstream analysis following Two-Sample MR (2S-MR). To explore drug repurposing opportunities, associations were assessed for therapeutic actionability and their status in clinical trials. CLL Chronic Lymphocytic Leukemia, DLBCL Diffuse Large B-cell Lymphoma, FL Follicular Lymphoma, HL Hodgkin Lymphoma, MM Multiple Myeloma, MZL Marginal Zone Lymphoma. Figure created with BioRender.com.

Fig. 2. Bubble plot of selected immune cell traits showing a relationship with at least one B-cell malignancy.

The columns correspond to the six B-cell malignancies. Bubble colors indicate the strength and direction of associations, with red corresponding to a positive association (i.e., higher expression linked to increased cancer risk) and blue corresponding to a negative association. Bubble size reflects the statistical significance of each association, measured by −log₁₀ of the P-value, with larger bubbles denoting more significant results. P-values are unadjusted and two-sided. Empty cells denote missing data for the corresponding B-cell malignancy. Tregs T regulatory cells.

Fig. 3. Cell surface markers showing a relationship with B-cell malignancy, categorized by cell type.

The B-cell malignancy-associated risk for a specific cell surface marker is represented by a circle placed next to the marker. The color of the circle indicates the direction of risk. For genetically predicted higher levels of the cell surface marker red signifies an increased risk, while green denotes decreased risk. Additionally, the clinical trial status for each potential drug target is displayed on the right-hand side of the figure, with assigned colored symbols representing the corresponding trial phase (Data retrieved from OpenTargets.org and ClinicalTrials.gov). Figure created with BioRender.com.

Fig. 4. Clinical trial status for each cell surface marker identified as potential candidate for therapeutic inhibition.

Each bar shows the clinical trial status of the cell surface marker as a drug target in B-cell malignancies as well as in solid tumors and non-neoplastic diseases. NHL (non-Hodgkin’s lymphoma FL, DLBCL, MZL), HL (Hodgkin lymphoma), MM (multiple myeloma), CLL (chronic lymphocytic leukemia). The left panel provides the status of six cell surface markers being targeted in advanced clinical trials (≥ Phase III) and which are approved for at least one condition. The right panel details the status of 12 markers which are primarily in early-phase trials. Created with BioRender.com.