Distinct exhaustion features of T lymphocytes shape the tumor-immune microenvironment with therapeutic implication in patients with non-small-cell lung cancer

Chang Gon Kim, Gamin Kim, Kyung Hwan Kim, Seyeon Park, Sunhye Shin, Dahee Yeo, Hyo Sup Shim, Hong In Yoon, Seong Yong Park, Sang Jun Ha, Hye Ryun Kim

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8 Citations (Scopus)


Reinvigoration of T-cell exhaustion with antibodies has shown promising efficacy in patients with non-small-cell lung cancer (NSCLC). However, the characteristics of T-cell exhaustion with regard to tumor-infiltrating lymphocytes (TILs) are poorly elucidated in NSCLC. Here, we investigated the exhaustion status of TILs in NSCLC patients at the intraindividual and interindividual levels. We obtained paired peripheral blood, normal adjacent tissues, peritumoral tissues, and tumor tissues from 96 NSCLC patients. Features of T-cell exhaustion were analyzed by flow cytometry. T cells were categorized according to their programmed cell death-1 (PD-1) expression (PD-1high, PD-1int, and PD-1negcells). Patients were classified based on the presence or absence of discrete PD-1highCD8+TILs. Production of effector cytokines by CD8+TILs was measured after T-cell stimulation with or without antibodies against immune checkpoint receptors. Progressive T-cell exhaustion with marked expression of exhaustion-related markers and diminished production of effector cytokines was observed in PD-1highCD8+TILs compared with PD-1intand PD-1negCD8+TILs. Patients with distinct PD-1highCD8+TILs (PD-1highexpressers) exhibited characteristics associated with a favorable anti-PD-1 response compared with those without these lymphocytes (non-PD-1highexpressers). Combined inhibition of dual immune checkpoint receptors further restored effector cytokine production by CD8+TILs following T-cell stimulation. PD-1highCD8+T lymphocyte populations in the peripheral blood and tumors were significantly correlated. T-cell exhaustion was differentially regulated among individual patients and was prominent in a subgroup of NSCLC patients who may benefit from PD-1 blockade or combined blockade of other immune checkpoint receptors.

Original languageEnglish
Article numbere002780
JournalJournal for ImmunoTherapy of Cancer
Issue number12
Publication statusPublished - 2021 Dec

Bibliographical note

Funding Information:
Funding This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation funded by the Ministry of Science and ICT (NRF-2019M3A9B6065231, 2017M3A9E802971, and 2017M3A9E9072669 to HRK and 2019M3A9B6065221, 2018R1A2A1A05076997, and 2017R1A5A1014560 to S-JH), Severance Hospital Research fund for Clinical excellence (C-2021-0016 to HRK), and Young Medical Scientist Research Grant Program of the Daewoong Foundation (DY20206P to CGK).

Publisher Copyright:
© 2021, BMJ Publishing Group Ltd. All rights reserved.

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research


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