Single-Cell Discovery and Multiomic Characterization of Therapeutic Targets in Multiple Myeloma

Abstract

Multiple myeloma (MM) is a highly refractory hematological cancer. Targeted immunotherapy has shown promise in MM but remains hindered by the challenge of identifying specific yet broadly representative tumor markers. We analyzed 53 bone marrow (BM) aspirates from 41 MM patients using an unbiased, high-throughput pipeline for therapeutic target discovery via single cell transcriptomic profiling, yielding 38 MM marker genes encoding cell-surface proteins and 15 encoding intracellular proteins. Of these, 20 candidate genes were highlighted that are not yet under clinical study, 11 of which are previously uncharacterized as therapeutic targets. The findings were cross-validated using bulk RNA-sequencing, flow cytometry, and proteomic mass spectrometry of MM cell lines and patient BM, demonstrating high overall concordance across data types. Independent discovery using bulk RNA-sequencing reiterated top candidates, further affirming the ability of single cell transcriptomics to accurately capture marker expression despite limitations in sample size or sequencing depth. Target dynamics and heterogeneity were further examined using both transcriptomic and immuno-imaging methods. In summary, this study presents a robust and broadly applicable strategy for identifying tumor markers to better inform the development of targeted cancer therapy.

Epigenetic regulation during cancer transitions across 11 tumour types

“…We performed snATAC-seq analysis of all 225 samples, along with paired single-cell or single-nucleus RNA-seq (sc/snRNA-seq) for 206 of these samples (Supplementary Table 1a). Among those, 14 scRNA-seq multiple myeloma (MM) samples, 10 snRNA-seq PDAC samples, 14 snRNA-seq glioblastoma (GBM) samples, and 28 snATAC-seq and 27 snRNA-seq clear-cell renal cell carcinoma (ccRCC) samples were obtained from previous studies [10][11][12][13] , with many of the ccRCC and GBM samples originating from the NCI Clinical Proteomic Tumour Analysis Consortium (CPTAC). Bulk whole-exome sequencing (WES) data were also generated for 195 samples (Supplementary Table 1a).…”

Antibody–drug conjugates transform the outcome of individuals with low‐HER2‐expression advanced breast cancer

“…Moreover, TRAEs in the SHR-A1811 group, such as hematologic toxicity and ILD/ pneumonia, occurred at lower rates. 25…”

“…All three patients who were previously administered single‐agent T‐DM1 demonstrated complete remission (CR) or partial remission (PR), resulting in an ORR of 100%. Moreover, TRAEs in the SHR‐A1811 group, such as hematologic toxicity and ILD/pneumonia, occurred at lower rates 25 . SHR‐A1811 is currently undergoing phase 1b/2 clinical trials to treat HER2 ultra‐low‐ or no‐expression MBC (NCT05824325, GALAXY).…”

Systems immunology spanning tumors, lymph nodes, and periphery

“…These analyses can be used to identify new cell states and markers for therapeutic targeting to develop more effective treatment interventions. 179 , 180 For instance, by molecularly profiling T cells and B cells for phenotypes in tandem with TCRs and BCRs, it is possible to classify B and T cells based on common and disparate characteristics to generate a comprehensive immune model of disease etiology and progression. 11 High-dimensional immunomics can also be used to examine immune responses to vaccines, checkpoint blockade, and other immunotherapies in development at high resolution, lending insights into how immune responses are modulated by these treatments.…”