Spatial transcriptomics reveals profound subclonal heterogeneity and T-cell dysfunction in extramedullary myeloma
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61988987%3A17110%2F24%3AA25039LY" target="_blank" >RIV/61988987:17110/24:A25039LY - isvavai.cz</a>
Alternative codes found
RIV/00843989:_____/24:E0111226
Result on the web
<a href="https://ashpublications.org/blood/article/144/20/2121/517469/Spatial-transcriptomics-reveals-profound-subclonal" target="_blank" >https://ashpublications.org/blood/article/144/20/2121/517469/Spatial-transcriptomics-reveals-profound-subclonal</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1182/blood.2024024590" target="_blank" >10.1182/blood.2024024590</a>
Alternative languages
Result language
angličtina
Original language name
Spatial transcriptomics reveals profound subclonal heterogeneity and T-cell dysfunction in extramedullary myeloma
Original language description
Extramedullary disease (EMD) is a high-risk feature of multiple myeloma (MM) and remains a poor prognostic factor, even in the era of novel immunotherapies. Here, we applied spatial transcriptomics (RNA tomography for spatially resolved transcriptomics [tomo-seq] [n = 2] and 10x Visium [n = 12]) and single-cell RNA sequencing (n = 3) to a set of 14 EMD biopsies to dissect the 3-dimensional architecture of tumor cells and their microenvironment. Overall, infiltrating immune and stromal cells showed both intrapatient and interpatient variations, with no uniform distribution over the lesion. We observed substantial heterogeneity at the copy number level within plasma cells, including the emergence of new subclones in circumscribed areas of the tumor, which is consistent with genomic instability. We further identified the spatial expression differences between GPRC5D and TNFRSF17, 2 important antigens for bispecific antibody therapy. EMD masses were infiltrated by various immune cells, including T cells. Notably, exhausted TIM3+/PD-1+ T cells diffusely colocalized with MM cells, whereas functional and activated CD8+ T cells showed a focal infiltration pattern along with M1 macrophages in tumor-free regions. This segregation of fit and exhausted T cells was resolved in the case of response to T-cell–engaging bispecific antibodies. MM and microenvironment cells were embedded in a complex network that influenced immune activation and angiogenesis, and oxidative phosphorylation represented the major metabolic program within EMD lesions. In summary, spatial transcriptomics has revealed a multicellular ecosystem in EMD with checkpoint inhibition and dual targeting as potential new therapeutic avenues.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30205 - Hematology
Result continuities
Project
<a href="/en/project/NU23-03-00374" target="_blank" >NU23-03-00374: Extramedullary multiple myeloma: molecular pathogenesis and novel therapeutical targets</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Blood
ISSN
0006-4971
e-ISSN
1528-0020
Volume of the periodical
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Issue of the periodical within the volume
20
Country of publishing house
US - UNITED STATES
Number of pages
15
Pages from-to
2121-2135
UT code for WoS article
001360802000001
EID of the result in the Scopus database
2-s2.0-85205803371