Characterization of t cell exhaustion in multiple myeloma = 다발골수종에서 소모성 T세포의 특성 규명

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Immune checkpoint inhibitors have shown therapeutic efficacy in various malignant diseases. However, anti-programmed death (PD)-1 monotherapy has not shown clinical efficacy in multiple myeloma (MM). I obtained bone marrow (BM) mononuclear cells from 52 newly diagnosed MM patients and examined the ex-pression profile of checkpoint receptors on BM $CD8^+$ T cells and their functional restoration by anti-PD-1. I confirmed upregulation of PD-1 and PD-L1 expression in $CD8^+$ T cells and myeloma cells, respectively, from the BM of MM patients. PD-1-expressing CD8+ T cells from the BM of MM patients co-expressed other checkpoint inhibitory receptors and exhibited a terminally differentiated phenotype represented by $Eomes^{hi}$T-$bet^{lo}$. These results were also observed in BM $CD8^+$ T cells specific to myeloma antigens NY-ESO-1 and HM1.24. BM $CD8^+$ T cells from MM patients exhibited reduced proliferation and cytokine production upon the stimulation of T-cell receptor signals compared to those from patients with other asymptomatic plasma-cell neoplasms and other B-cell lymphomas. However, anti-PD-1 did not increase the proliferation of BM $CD8^+$ T cells from MM patients, but it increased the proliferation of those cells from other $\beta$-cell lympho-mas, indicating that the T-cell exhaustion in MM is hardly reversed by PD-1 blockade alone. Intriguingly, anti-PD-1 significantly increased the proliferation and cytokine production of BM $CD8^+$ T cells from MM patients in the presence of transforming growth factor-$\beta$ (TGF-$\beta$) inhibitors, such as anti-TGF-$\beta$1 blocking antibodies and TGF-$\beta$ receptor-1 inhibitor, suggesting that the combined blockade of PD-1 and TGF-$\beta$ may be useful for the treatment of MM.
Advisors
Shin, Eui-Cheolresearcher신의철researcherPark, Su-Hyungresearcher박수형researcher
Description
한국과학기술원 :의과학대학원,
Publisher
한국과학기술원
Issue Date
2019
Identifier
325007
Language
eng
Description

학위논문(박사) - 한국과학기술원 : 의과학대학원, 2019.2,[1책 :]

Keywords

CD8 T cell▼amultiple myeloma▼aPD-1▼aTGF-$\beta$▼aT cell exhaustion▼aantigen-specific T cell; CD8 T 세포▼a다발골수종▼aPD-1▼aTGF-$\beta$▼aT 세포 소모▼a항원 특이 T 세포

URI
http://hdl.handle.net/10203/265094
Link
http://library.kaist.ac.kr/search/detail/view.do?bibCtrlNo=842190&flag=dissertation
Appears in Collection
MSE-Theses_Ph.D.(박사논문)
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