Longitudinal Profiling of Tumor and Immune Compartments Uncovers Patterns of Dysregulation and Associations with Response in Multiple Myeloma
Year: 2025
Type: article
Study design: Observational Study
Abstract: Multiple myeloma is a malignancy of clonally expanded plasma cells shaped by complex interactions with the immune microenvironment (IME). To investigate immune correlates of treatment response and disease progression, we conducted multi-omics profiling including CD138neg single-cell RNA sequencing of 243 bone marrow samples from 102 patients (631,226 cells) and CD138pos bulk RNA and whole-genome sequencing from 209 samples. In longitudinal analyses, interferon-γ signaling associated with markers of impaired T-cell memory after autologous stem cell transplant, whereas naïve B-cell abundance and immunoglobulin diversity correlated with improved progression-free survival (HR = 0.48; P = 2.3e-4). At disease progression, multiple myeloma cells upregulated cancer-testis antigens (CTAg) and immune effector genes, with concurrent B-cell depletion, enrichment of myeloid-derived suppressor cell expression, and phenotypic T-cell exhaustion. These findings highlight dynamic immune-tumor interactions, identifying naïve B-cell reconstitution as a biomarker of durable response and CTAgs as potential targets for high-risk disease at progression. SIGNIFICANCE: Longitudinal profiling of multiple myeloma and the IME revealed dynamic immune-tumor interactions across the disease course. Altered expression in CD8+ T cells limited memory phenotype after transplant, whereas naïve B-cell recovery associated with sustained treatment response. At progression, CTAg expression associated with immunosuppression, revealing novel mechanisms of immune dysregulation.
Source: Blood Cancer Discovery
Authors: Denis J. Ohlstrom, William C. Pilcher, Marina E. Michaud, Chaitanya Acharya, Sarthak Satpathy, Edgar Gonzalez-Kozlova, Reyka G. Jayasinghe, Katherine Ferguson, Hope L. Mumme, Shivani Nanda, Yizhe Song, Sowmitri Mantrala, Dimitra Karagkouni, Jessica Schulman, Nick Pabustan, Junia Vieira Dos Santos, Daniel W. Sherbenou, Jonathan J. Keats, Alexander M. Gout, Steven Foltz, Alessandro Lagana, Taxiarchis Kourelis, Ravi Vij, Madhav V. Dhodapkar, David Avigan, Hearn Jay Cho, Linda B. Baughn, Ajay K. Nooka, Sagar Lonial, Shaji Kumar, Mehmet K. Samur, Ioannis S. Vlachos, Li Ding, Sacha Gnjatic, George Mulligan, Manoj K. Bhasin
Institutions: Georgia Institute of Technology, Emory University, The Wallace H. Coulter Department of Biomedical Engineering, Multiple Myeloma Research Foundation, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Washington University in St. Louis, Broad Institute, Beth Israel Deaconess Medical Center, Harvard University, University of Colorado Anschutz, Translational Genomics Research Institute, Mayo Clinic, Fred Hutch Cancer Center, Winship Cancer Institute, Children's Healthcare of Atlanta, Dana-Farber Cancer Institute
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Multiple Myeloma Research Foundation, Bristol-Myers Squibb, Pfizer, Sanofi, Celgene, Kowa Company, Paula and Rodger Riney Foundation, National Institutes of Health, Genentech, Harvard Stem Cell Institute, Chugai Pharmaceutical, Kite Pharma, Pharmacyclics, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1831948088, G20952977, G3174663377, G4847734291, G707968403, Washington University Human Tumor Atlas Research Center, G9000007950, G9000091667, G9000141548, G9000295549, Integrative Oncogenomics of Multiple Myeloma, Paul Calabresi Program in Clinical/Translational Research at Mayo Clinic, Pan-Cancer characterization of 3’UTR somatic mutations controlling tumor immune evasion
OpenAlex ID: W4417170959