Exhausted status and anti-PD-1 response of tumor-infiltrating $CD8^+$ T cells in patients with glioblastoma = 교모세포종 환자의 종양 침윤 $CD8^+$ T 세포의 면역 탈진 상태와 PD-1 억제제에 의해 유도되는 기능 회복에 관한 연구

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Glioblastoma(GBM) is the most common and aggressive primary malignant brain tumor and has a poor prognosis. Recently, Immune checkpoint inhibitors (ICIs) are used for the treatment of various cancers, but clinical trials of anti-PD-1 with recurrent GBM patients have failed to show clinical benefits. Several factors may limit the efficacy of ICIs, including the exhaustion status of tumor-infiltrating lymphocytes (TILs). Therefore, in this study, we examined the differentiation status of $CD8^+$ TILs from primary GBM patients and their reinvigoration by ICIs to understand the nature of T-cell exhaustion in GBM. I isolated TILs from 98 patients with newly diagnosed GBM and found that $CD8^+$ TILs had significantly increased expression of immune checkpoint receptors, compared to peripheral blood $CD8^+$ T cells. Among $CD8^+$ TILs, $PD-1^+$ cells exhibited more terminally differentiated phenotypes than PD-1- cells. Evaluating the anti-PD-1-induced reinvigoration of $CD8^+$ TILs after ex vivo stimulation with anti-CD3 and anti-PD-1, I found that reinvigoration inversely correlated with the percentage of $Eomes^{hi} T-bet^{lo}$ cells among $PD-1^+CD8^+$ TILs. When anti-CTLA-4 was used in combination with anti-PD-1, an additional increase in $CD8^+$ TIL proliferation was not observed in patients who did not respond to anti-PD-1. Therefore, in primary GBM, the differentiation status of $CD8^+$ TILs determines their reinvigoration ability upon ICI treatment. To explore the possibility of novel strategy, I combined anti-PD-1 with galunisertib, one of the promising TGF-$\beta$ blockers. Galunisertib could reinvigorate $CD8^+$ TILs regardless of the response to anti-PD-1. In addition, the reinvigoration effect of combined anti-PD-1 with galunisertib was more prominent in the ‘low responding TILs’ group compared to the ‘high responding TILs’ group. The present study may provide the rationale and evidence for establishing optimal strategies for combinational ICI treatment in patients with GBM.
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,[vi, 79 p. :]

Keywords

교모세포종▼aT 세포▼aPD-1▼aCTLA-4▼a분화; Glioblastoma▼aT cell▼aPD-1▼aCTLA-4▼adifferentiation

URI
http://hdl.handle.net/10203/265095
Link
http://library.kaist.ac.kr/search/detail/view.do?bibCtrlNo=842196&flag=dissertation
Appears in Collection
MSE-Theses_Ph.D.(박사논문)
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