Progression of AITL-like tumors in mice is driven by Tfh signature proteins and T-B cross talk.
Journal
Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425
Informations de publication
Date de publication:
10 03 2020
10 03 2020
Historique:
received:
18
10
2019
accepted:
05
02
2020
entrez:
5
3
2020
pubmed:
5
3
2020
medline:
15
5
2021
Statut:
ppublish
Résumé
Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive peripheral T-cell lymphoma driven by a pool of neoplastic cells originating from T follicular helper (Tfh) cells and concomitant expansion of B cells. Conventional chemotherapies for AITL have shown limited efficacy, and as such, there is a need for improved therapeutic options. Because AITL originates from Tfh cells, we hypothesized that AITL tumors continue to rely on essential Tfh components and intimate T-cell-B-cell (T-B) interactions. Using a spontaneous AITL mouse model (Roquinsan/+ mice), we found that acute loss of Bcl6 activity in growing tumors drastically reduced tumor size, demonstrating that AITL-like tumors critically depend on the Tfh lineage-defining transcription factor Bcl6. Because Bcl6 can upregulate expression of signaling lymphocytic activation molecule-associated protein (SAP), which is known to promote T-B conjugation, we next targeted the SAP-encoding Sh2d1a gene. We observed that Sh2d1a deletion from CD4+ T cells in fully developed tumors also led to tumor regression. Further, we provide evidence that tumor progression depends on T-B cross talk facilitated by SAP and high-affinity LFA-1. In our study, AITL-like tumors relied heavily on molecular pathways that support Tfh cell identity and T-B collaboration, revealing potential therapeutic targets for AITL.
Identifiants
pubmed: 32130407
pii: S2473-9529(20)31451-8
doi: 10.1182/bloodadvances.2019001114
pmc: PMC7065475
doi:
Substances chimiques
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
868-879Subventions
Organisme : CIHR
ID : MT-14429
Pays : Canada
Organisme : CIHR
ID : MOP-82906
Pays : Canada
Organisme : CIHR
ID : FDN-143338
Pays : Canada
Informations de copyright
© 2020 by The American Society of Hematology.
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