Single Cell Clonotypic and Transcriptional Evolution of Multiple Myeloma Precursor Disease

Dang, Minghao; Han, Guangchun; Lee, Hans C.; Patel, Krina; Thomas, Sheeba K.; Hao, Dapeng; Chu, Yanshuo; Becnel, Melody; Weber, Donna M.; Lin, Pei; Lutter-Berka, Zuzana; Nolasco, David Berrios; Song, Xingzhi; Zhang, Jianhua; Futreal, P. Andrew; Rueda, Yurany Moreno; Symer, David E.; Green, Michael; Rojas‐Hernandez, Cristhiam M.; Kroll, Michael H.; Afshar-Kharghan, Vashir; Ndacayisaba, Libere J.; Kühn, Peter; Neelapu, Sattva S.; Orłowski, Robert Z.; Wang, Linghua; Manasanch, Elisabet E.

doi:10.2139/ssrn.4261550

Cited by 3 publications

(4 citation statements)

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“…We show myeloma is associated with an enrichment of terminally differentiated clonal memory T-cells. This analysis extends previous reports 14,21,46 by demonstrating an independence from age and showing concurrent changes to the TCR repertoire and systemic T-cell compartment. These alterations are similar to T-cell immunosenescence changes seen during aging 12 , meaning SMM and MM patients have prematurely aged T-cell compartments (Fig.…”

Section: Myeloma-associated T-cell Differentiation Possesses Features...supporting

confidence: 89%

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Tumour-intrinsic features shape T-cell differentiation through myeloma disease evolution

Foster,

Rees,

Ainley

et al. 2024

Preprint

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The haematological malignancy multiple myeloma is associated with skewed T-cell activation and function. T-cell alterations are detectable in asymptomatic myeloma precursor conditions and have the potential to identify precursor patients at imminent risk of progression. However, what myeloma-associated T-cells alterations represent mechanistically, how they relate to tumour burden and gene expression, and what influences high inter-patient variability in immune composition remains unknown. Here, we assembled the largest ever dataset of published and newly-generated single-cell RNA and TCR sequencing of the marrow and blood from patients with myeloma, precursor conditions, and age-matched non-cancer controls. We show myeloma is not associated with T-cell exhaustion and instead defined by a pattern of T-cell differentiation resembling antigen-driven terminal memory differentiation. Myeloma-associated T-cell differentiation was dependent on tumour-intrinsic features including tumour burden and tumour expression of antigen-presentation genes. Expanded TCR clones accumulating in myeloma were not enriched for viral specificity and were detected in effector states in highly infiltrated marrows. Together, these results suggest anti-tumour immunity drives a novel form of cancer-associated T-cell memory differentiation in myeloma.

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Section: Myeloma-associated T-cell Differentiation Possesses Features...supporting

confidence: 89%

“…While we were unable to compare T-cells features and tumour genomic classification in our dataset, T-cell skewing was previously shown to be enhanced in hyperdiploid patients 46 .…”

Section: Myeloma-associated T-cell Differentiation Possesses Features...mentioning

confidence: 83%

Tumour-intrinsic features shape T-cell differentiation through myeloma disease evolution

Foster,

Rees,

Ainley

et al. 2024

Preprint

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“…MM is a tumor originating from the immune system and highly sensitive to immunomodulators, with high ITH and interindividual heterogeneity. 49 Our study focused on patients with high ITH and found that the phenomenon of neoantigen loss was closely related to the duration and depth of remission for patients with first-line therapy. For patients with low neoantigen loss, long-term remission can be achieved through drug therapy.…”

Section: Discussionmentioning

confidence: 93%

The loss of neoantigens is an important reason for immune escape in multiple myeloma patients with high intratumor heterogeneity

Wang,

Xu,

Lan

et al. 2023

Cancer Medicine

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ObjectivesIntratumor heterogeneity (ITH) is an important factor for clinical outcomes in patients with multiple myeloma (MM). High ITH has been proven to be a key reason for tumor immune escape and treatment resistance. Neoantigens are thought to be associated with ITH, but the specific correlation and functional basis for this remains unclear.MethodsWe study this question through the whole‐exome sequencing (WES) data from 43 high ITH newly diagnosed MM patients in our center. Mutant allele tumor heterogeneity (MATH) was conducted to quantify ITH. The cutoff value for high intratumor heterogeneity was determined by comparing MATH of different kinds of tumors. NeoPredPipe was performed to predict neoantigens and binding affinity.ResultsCompared to other tumors, MM has a relatively low tumor mutation burden but a high ITH. Patients with high MATH had significantly shorter progression‐free survival times than those with low MATH (p = 0.001). In high ITH samples, there is a decrease in strong‐binding neoantigens (p = 0.019). The loss of strong‐binding neoantigens is a key factor for insensitivity to therapy (p = 0.015). Loss of heterozygosity in HLA was not observed. In addition, patients with fewer neoantigens loss had higher rates of disease remission (p = 0.047). CD8 + T cells (p = 0.012) and NK cells (p = 0.011) decreased significantly in patients with high neoantigens loss rate. A prediction model based on neoantigens was built to evaluate the strength of immune escape.ConclusionThe loss of strong‐binding neoantigens explains why tumors with high ITH have a higher degree of immune escape and may be feasible for deciding the clinical treatment of MM.

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“…At an extremely high resolution, precursor clones of various tumors have been identified, and co-evolutionary dynamics of the transformed cells and their microenvironment are being depicted. Furthermore, integrative analyses of paired omics modalities, such as genome, epigenome, and transcriptome, have been preliminarily applied to map the early tumorigenesis events, 117,135,302,452 offering insights into the ordering and interplays among multiple evolutionary drivers, as well as their roles in regulating cellular phenotype. As multiplexing spatial and single-cell multi-omics technologies continue to enhance their throughput, resolution, and accuracy, coupled with innovations in bioinformatics tools to analyze unprecedented high-dimensional data, 453 it is anticipated that multi-omics approaches can be leveraged to achieve a more comprehensive understanding of the complex biological processes of tumorigenesis.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets

Zhang,

Xiao,

et al. 2024

Sig Transduct Target Ther

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Tumorigenesis is a multistep process, with oncogenic mutations in a normal cell conferring clonal advantage as the initial event. However, despite pervasive somatic mutations and clonal expansion in normal tissues, their transformation into cancer remains a rare event, indicating the presence of additional driver events for progression to an irreversible, highly heterogeneous, and invasive lesion. Recently, researchers are emphasizing the mechanisms of environmental tumor risk factors and epigenetic alterations that are profoundly influencing early clonal expansion and malignant evolution, independently of inducing mutations. Additionally, clonal evolution in tumorigenesis reflects a multifaceted interplay between cell-intrinsic identities and various cell-extrinsic factors that exert selective pressures to either restrain uncontrolled proliferation or allow specific clones to progress into tumors. However, the mechanisms by which driver events induce both intrinsic cellular competency and remodel environmental stress to facilitate malignant transformation are not fully understood. In this review, we summarize the genetic, epigenetic, and external driver events, and their effects on the co-evolution of the transformed cells and their ecosystem during tumor initiation and early malignant evolution. A deeper understanding of the earliest molecular events holds promise for translational applications, predicting individuals at high-risk of tumor and developing strategies to intercept malignant transformation.

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Single Cell Clonotypic and Transcriptional Evolution of Multiple Myeloma Precursor Disease

Cited by 3 publications

References 0 publications

Tumour-intrinsic features shape T-cell differentiation through myeloma disease evolution

Tumour-intrinsic features shape T-cell differentiation through myeloma disease evolution

The loss of neoantigens is an important reason for immune escape in multiple myeloma patients with high intratumor heterogeneity

Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets

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