Multiple myeloma (MM) is an incurable malignancy of clonally expanded plasma cells shaped by complex interactions with the immune microenvironment. To investigate immune factors driving treatment response and resistance, 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. Longitudinal analyses revealed that interferon gamma signaling impairs T cell memory after autologous stem cell transplant, while naïve B cell abundance and immunoglobulin diversity correlated with improved progression-free survival (HR = 0.48, p = 2.3e-4). At disease progression, MM cells upregulated cancer-testis antigens and immune effector genes, with concurrent B cell depletion, enrichment of myeloid-derived suppressor cell genes in monocytes, and T cell exhaustion. These findings highlight dynamic immune-tumor interactions, identifying naïve B cell reconstitution as a biomarker of durable response, and cancer-testis antigens as potential targets for high-risk disease at progression. Statement of Significance Longitudinal profiling of multiple myeloma and the immune microenvironment revealed dynamic immune-tumor interactions across the disease course. Dysfunctional CD8⁺ T cells limited memory formation post-transplant, while naïve B recovery associated with sustained treatment response. At progression, cancer-testis antigen expression associated with immunosuppression, revealing novel mechanisms of immune escape. ### Competing Interest Statement SG reports other research funding from Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Genentech, Regeneron, and Takeda, and consulting from Taiho Pharmaceuticals, not related to this study. SK declares Research funding for clinical trials to the institution: Abbvie, Amgen, Allogene, BMS, Carsgen, GSK, Janssen, Roche-Genentech, Takeda, Regeneron Consulting/Advisory Board participation: (with no personal payments) Abbvie, BMS, Janssen, Roche-Genentech, Takeda, Pfizer, Loxo Oncology, K36, Sanofi, ArcellX, Beigene; TK declares research funding from Novartis, Pfizer. Advisory Board: BMS. DA declares grants from MMRF, CTN (NIHLBI), Celgene, Pharmacyclics and Kite Pharma. Other support from Juno, Partners TX, Karyopharm, BMS, Aviv MedTech Ltd., Takeda, Legend Bio Tech, Chugai, Caribou Biosciences, Janssen, Parexel, Sanofi, and Kowa.; DA has a patent for PCT/US2021/059199 pending.; ISV reports grants from NCI, NHLBI, NIDDK, Harvard Stem Cell Institute, and consulting for Mosaic LLC, AlphaSights, NextRNA, and Guidepoint Global outside of the submitted work; Other authors declare no competing financial or non-financial interests.
Despite advancements in understanding the pathophysiology of Multiple Myeloma (MM), the cause of rapid progressing disease in a subset of patients is still unclear. MM’s progression is facilitated by complex interactions with the surrounding bone marrow (BM) cells, forming a microenvironment that supports tumor growth and drug resistance. Understanding the immune microenvironment is key to identifying factors that promote rapid progression of MM. To accomplish this, we performed a multi-center single-cell RNA sequencing (scRNA-seq) study on 102,207 cells from 48 CD138 - BM samples collected at the time of disease diagnosis from 18 patients with either rapid progressing (progression-free survival (PFS) < 18 months) or non-progressing (PFS > 4 years) disease. Comparative analysis of data from three centers demonstrated similar transcriptome profiles and cell type distributions, indicating subtle technical variation in scRNA-seq, opening avenues for an expanded multicenter trial. Rapid progressors depicted significantly higher enrichment of GZMK + and TIGIT + exhausted CD8 + T-cells ( P = 0.022) along with decreased expression of cytolytic markers ( PRF1, GZMB, GNLY ). We also observed a significantly higher enrichment of M2 tolerogenic macrophages in rapid progressors and activation of pro-proliferative signaling pathways, such as BAFF, CCL, and IL16. On the other hand, non-progressive patients depicted higher enrichment for immature B Cells (i.e., Pre/Pro B cells), with elevated expression for markers of B cell development ( IGLL1 , SOX4 , DNTT ). This multi-center study identifies the enrichment of various pro-tumorigenic cell populations and pathways in those with rapid progressing disease and further validates the robustness of scRNA-seq data generated at different study centers.
Introduction Copy number abnormalities (CNA) and structural variants (SV) are crucial to driving cancer progression and in multiple myeloma (MM). Chr1 CNA are seen in up to 40% of cases and associate with poor prognosis. Variants include deletions, gains, translocations and complex SV events such as chromothripsis (CT), chromoplexy (CP) and templated insertions (TI) which result in aberrant transcriptional patterns. Abnormal expression of genes on chr1 lead to the adverse clinical outcome and studies focussed on 1p12, 1p32.3 and 1q12-21 identified potential causal genes including TENT5C, CDKN2C, CKS1B, PDZK1, BCL9, ANP32E, ILF2, ADAR, MDM2 and MCL1 but none fully explain the clinical behavior. To address this deficiency and to relate chromatin structure to gene deregulation we present a multiomic bioinformatic analysis of SV, CNA, mutation and expression changes in relation to the chromatin structure of chr1.
Abstract In 2020, the Noble Prize for Medicine jointly went to three scientists for hepatitis C virus-related discoveries. Earlier in 1976, an American scientist won this award for the discovery of hepatitis B virus. The Noble Prize, constituted as per the will of Alfred Noble, is awarded every year for achievements that benefit human beings in the best possible way. Although humans have known hepatitis as a deadly disease for hundreds of years, it was the discovery of hepatitis B and C viruses that changed the way we knew the hepatitis viruses forever and paved the way for saving millions of lives all over the world, the reason why the Noble Committee has on two different occasions picked up the great minds behind the discovery of these two hepatitis viruses and recognized them by conferring them with the highest recognition that one dreams of. How to cite this article: Al-Mahtab M, Roy PP, Khan MSI, et al. Nobel Prize for the Discovery of Hepatitis B and C: A Brief History in Time. Euroasian J Hepatogastroenterol 2020;10(2):98–100.
