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

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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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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Park, J., Kwon, M., Kim, K. H., Kim, T. S., Hong, S. H., Kim, C. G., Kang, S. G., Moon, J. H., Kim, E. H., Park, S. H., Chang, J. H., & Shin, E. C. (2019). Immune checkpoint inhibitor-induced reinvigoration of tumor-infiltrating CD8+ T cells is determined by their differentiation status in glioblastoma. Clinical Cancer Research, 25(8), 2549-2559. https://doi.org/10.1158/1078-0432.CCR-18-2564