Oncogenic Calreticulin Induces Immune Escape by Stimulating TGFß Expression and Regulatory T-cell Expansion in the Bone Marrow Microenvironment.
Cancer Res
; 84(18): 2985-3003, 2024 Sep 16.
Article
em En
| MEDLINE
| ID: mdl-38885318
ABSTRACT
Increasing evidence supports the interplay between oncogenic mutations and immune escape mechanisms. Strategies to counteract the immune escape mediated by oncogenic signaling could provide improved therapeutic options for patients with various malignancies. As mutant calreticulin (CALR) is a common driver of myeloproliferative neoplasms (MPN), we analyzed the impact of oncogenic CALRdel52 on the bone marrow (BM) microenvironment in MPN. Single-cell RNA sequencing revealed that CALRdel52 led to the expansion of TGFß1-producing erythroid progenitor cells and promoted the expansion of FoxP3+ regulatory T cells (Treg) in a murine MPN model. Treatment with an anti-TGFß antibody improved mouse survival and increased the glycolytic activity in CD4+ and CD8+ T cells in vivo, whereas T-cell depletion abrogated the protective effects conferred by neutralizing TGFß. TGFß1 reduced perforin and TNFα production by T cells in vitro. TGFß1 production by CALRdel52 cells was dependent on JAK1/2, PI3K, and ERK activity, which activated the transcription factor Sp1 to induce TGFß1 expression. In four independent patient cohorts, TGFß1 expression was increased in the BM of patients with MPN compared with healthy individuals, and the BM of patients with MPN contained a higher frequency of Treg compared with healthy individuals. Together, this study identified an ERK/Sp1/TGFß1 axis in CALRdel52 MPNs as a mechanism of immunosuppression that can be targeted to elicit T-cell-mediated cytotoxicity. Significance:
Targeting the mutant calreticulin/TGFß1 axis increases T-cell activity and glycolytic capacity, providing the rationale for conducting clinical trials on TGFß antagonists as an immunotherapeutic strategy in patients with myeloproliferative neoplasms.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfócitos T Reguladores
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Calreticulina
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Microambiente Tumoral
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Transtornos Mieloproliferativos
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article