Immune checkpoint inhibitor-induced reinvigoration of tumor-infiltrating CD8+ T cells is determined by their differentiation status in glioblastoma

Junsik Park, Minsuk Kwon, Kyung Hwan Kim, Tae Shin Kim, Seon Hui Hong, Chang Gon Kim, Seok-Gu Kang, Ju Hyung Moon, Eui Hyun Kim, Su Hyung Park, Jong Hee Chang, Eui Cheol Shin

Research output: Contribution to journalArticle

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Abstract

Purpose: Immune checkpoint inhibitors (ICI) are used for the treatment of various cancers, but clinical trials of antiprogrammed cell death protein 1 (PD-1) with patients with recurrent glioblastoma (GBM) have failed to show clinical benefits. In this study, we examined the differentiation status of CD8+ tumor-infiltrating lymphocytes (TIL) from patients with primary GBM and their reinvigoration by ICIs to understand the nature of T-cell exhaustion in GBM. Experimental Design: We isolated TILs from 98 patients with newly diagnosed GBM and examined the expression of immune checkpoint receptors and T-cell transcription factors using flow cytometry. TILs were ex vivo stimulated with anti-CD3 in the presence of anti-PD-1 and/or anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) and their proliferation assessed. Results:CD8+ TILs had significantly increased expression of immune checkpoint receptors, including PD-1 and CTLA-4, compared with peripheral blood CD8+ T cells. Among CD8+ TILs, PD-1+ cells exhibited more terminally differentiated phenotypes (i.e., EomeshiT-betlo) than PD-1- cells. These data were confirmed by analyzing NY-ESO-1157- specific CD8+ TILs. Evaluating the proliferation of CD8+ TILs after ex vivo stimulation with anti-CD3 and anti-PD-1, we found that proliferation inversely correlated with the percentage of EomeshiT-betlo 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 observed in patients with low percentages of EomeshiT-betlo CD8+ TILs, who responded well to anti-PD-1 in ex vivo assays, but not in patients with high percentages of EomeshiT-betlo CD8+ TILs, who did not respond to anti-PD-1. Conclusions: In primary GBM, the differentiation status of CD8+ TILs determines their reinvigoration ability upon ICI treatment.

Original languageEnglish
Pages (from-to)2549-2559
Number of pages11
JournalClinical Cancer Research
Volume25
Issue number8
DOIs
Publication statusPublished - 2019 Apr 15

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Glioblastoma
CTLA-4 Antigen
T-Lymphocytes
Tumor-Infiltrating Lymphocytes
Neoplasms
Programmed Cell Death 1 Receptor
TCF Transcription Factors
Flow Cytometry
Cell Death
Research Design
Transcription Factors
Clinical Trials
Phenotype
Therapeutics
Proteins
Thomsen-Friedenreich antibodies

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Park, Junsik ; Kwon, Minsuk ; Kim, Kyung Hwan ; Kim, Tae Shin ; Hong, Seon Hui ; Kim, Chang Gon ; Kang, Seok-Gu ; Moon, Ju Hyung ; Kim, Eui Hyun ; Park, Su Hyung ; Chang, Jong Hee ; Shin, Eui Cheol. / Immune checkpoint inhibitor-induced reinvigoration of tumor-infiltrating CD8+ T cells is determined by their differentiation status in glioblastoma. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 8. pp. 2549-2559.
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abstract = "Purpose: Immune checkpoint inhibitors (ICI) are used for the treatment of various cancers, but clinical trials of antiprogrammed cell death protein 1 (PD-1) with patients with recurrent glioblastoma (GBM) have failed to show clinical benefits. In this study, we examined the differentiation status of CD8+ tumor-infiltrating lymphocytes (TIL) from patients with primary GBM and their reinvigoration by ICIs to understand the nature of T-cell exhaustion in GBM. Experimental Design: We isolated TILs from 98 patients with newly diagnosed GBM and examined the expression of immune checkpoint receptors and T-cell transcription factors using flow cytometry. TILs were ex vivo stimulated with anti-CD3 in the presence of anti-PD-1 and/or anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) and their proliferation assessed. Results:CD8+ TILs had significantly increased expression of immune checkpoint receptors, including PD-1 and CTLA-4, compared with peripheral blood CD8+ T cells. Among CD8+ TILs, PD-1+ cells exhibited more terminally differentiated phenotypes (i.e., EomeshiT-betlo) than PD-1- cells. These data were confirmed by analyzing NY-ESO-1157- specific CD8+ TILs. Evaluating the proliferation of CD8+ TILs after ex vivo stimulation with anti-CD3 and anti-PD-1, we found that proliferation inversely correlated with the percentage of EomeshiT-betlo 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 observed in patients with low percentages of EomeshiT-betlo CD8+ TILs, who responded well to anti-PD-1 in ex vivo assays, but not in patients with high percentages of EomeshiT-betlo CD8+ TILs, who did not respond to anti-PD-1. Conclusions: In primary GBM, the differentiation status of CD8+ TILs determines their reinvigoration ability upon ICI treatment.",
author = "Junsik Park and Minsuk Kwon and Kim, {Kyung Hwan} and Kim, {Tae Shin} and Hong, {Seon Hui} and Kim, {Chang Gon} and Seok-Gu Kang and Moon, {Ju Hyung} and Kim, {Eui Hyun} and Park, {Su Hyung} and Chang, {Jong Hee} and Shin, {Eui Cheol}",
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Immune checkpoint inhibitor-induced reinvigoration of tumor-infiltrating CD8+ T cells is determined by their differentiation status in glioblastoma. / Park, Junsik; Kwon, Minsuk; Kim, Kyung Hwan; Kim, Tae Shin; Hong, Seon Hui; Kim, Chang Gon; Kang, Seok-Gu; Moon, Ju Hyung; Kim, Eui Hyun; Park, Su Hyung; Chang, Jong Hee; Shin, Eui Cheol.

In: Clinical Cancer Research, Vol. 25, No. 8, 15.04.2019, p. 2549-2559.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Immune checkpoint inhibitor-induced reinvigoration of tumor-infiltrating CD8+ T cells is determined by their differentiation status in glioblastoma

AU - Park, Junsik

AU - Kwon, Minsuk

AU - Kim, Kyung Hwan

AU - Kim, Tae Shin

AU - Hong, Seon Hui

AU - Kim, Chang Gon

AU - Kang, Seok-Gu

AU - Moon, Ju Hyung

AU - Kim, Eui Hyun

AU - Park, Su Hyung

AU - Chang, Jong Hee

AU - Shin, Eui Cheol

PY - 2019/4/15

Y1 - 2019/4/15

N2 - Purpose: Immune checkpoint inhibitors (ICI) are used for the treatment of various cancers, but clinical trials of antiprogrammed cell death protein 1 (PD-1) with patients with recurrent glioblastoma (GBM) have failed to show clinical benefits. In this study, we examined the differentiation status of CD8+ tumor-infiltrating lymphocytes (TIL) from patients with primary GBM and their reinvigoration by ICIs to understand the nature of T-cell exhaustion in GBM. Experimental Design: We isolated TILs from 98 patients with newly diagnosed GBM and examined the expression of immune checkpoint receptors and T-cell transcription factors using flow cytometry. TILs were ex vivo stimulated with anti-CD3 in the presence of anti-PD-1 and/or anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) and their proliferation assessed. Results:CD8+ TILs had significantly increased expression of immune checkpoint receptors, including PD-1 and CTLA-4, compared with peripheral blood CD8+ T cells. Among CD8+ TILs, PD-1+ cells exhibited more terminally differentiated phenotypes (i.e., EomeshiT-betlo) than PD-1- cells. These data were confirmed by analyzing NY-ESO-1157- specific CD8+ TILs. Evaluating the proliferation of CD8+ TILs after ex vivo stimulation with anti-CD3 and anti-PD-1, we found that proliferation inversely correlated with the percentage of EomeshiT-betlo 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 observed in patients with low percentages of EomeshiT-betlo CD8+ TILs, who responded well to anti-PD-1 in ex vivo assays, but not in patients with high percentages of EomeshiT-betlo CD8+ TILs, who did not respond to anti-PD-1. Conclusions: In primary GBM, the differentiation status of CD8+ TILs determines their reinvigoration ability upon ICI treatment.

AB - Purpose: Immune checkpoint inhibitors (ICI) are used for the treatment of various cancers, but clinical trials of antiprogrammed cell death protein 1 (PD-1) with patients with recurrent glioblastoma (GBM) have failed to show clinical benefits. In this study, we examined the differentiation status of CD8+ tumor-infiltrating lymphocytes (TIL) from patients with primary GBM and their reinvigoration by ICIs to understand the nature of T-cell exhaustion in GBM. Experimental Design: We isolated TILs from 98 patients with newly diagnosed GBM and examined the expression of immune checkpoint receptors and T-cell transcription factors using flow cytometry. TILs were ex vivo stimulated with anti-CD3 in the presence of anti-PD-1 and/or anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) and their proliferation assessed. Results:CD8+ TILs had significantly increased expression of immune checkpoint receptors, including PD-1 and CTLA-4, compared with peripheral blood CD8+ T cells. Among CD8+ TILs, PD-1+ cells exhibited more terminally differentiated phenotypes (i.e., EomeshiT-betlo) than PD-1- cells. These data were confirmed by analyzing NY-ESO-1157- specific CD8+ TILs. Evaluating the proliferation of CD8+ TILs after ex vivo stimulation with anti-CD3 and anti-PD-1, we found that proliferation inversely correlated with the percentage of EomeshiT-betlo 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 observed in patients with low percentages of EomeshiT-betlo CD8+ TILs, who responded well to anti-PD-1 in ex vivo assays, but not in patients with high percentages of EomeshiT-betlo CD8+ TILs, who did not respond to anti-PD-1. Conclusions: In primary GBM, the differentiation status of CD8+ TILs determines their reinvigoration ability upon ICI treatment.

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