Aging- and Tumor-Mediated Increase in CD8+CD28- T Cells Might Impose a Strong Barrier to Success of Immunotherapy in Glioblastoma

Immunohorizons. 2021 Jun 8;5(6):395-409. doi: 10.4049/immunohorizons.2100008.

Abstract

Clinical use of various forms of immunotherapeutic drugs in glioblastoma (GBM), has highlighted severe T cell dysfunction such as exhaustion in GBM patients. However, reversing T cell exhaustion using immune checkpoint inhibitors in GBM clinical trials has not shown significant overall survival benefit. Phenotypically, CD8+ T cells with downregulated CD28 coreceptors, low CD27 expression, increased CD57 expression, and telomere shortening are classified as senescent T cells. These senescent T cells are normally seen as part of aging and also in many forms of solid cancers. Absence of CD28 on T cells leads to several functional irregularities including reduced TCR diversity, incomplete activation of T cells, and defects in Ag-induced proliferation. In the context of GBM, presence and/or function of these CD8+CD28- T cells is unknown. In this clinical correlative study, we investigated the effect of aging as well as tumor microenvironment on CD8+ T cell phenotype as an indicator of its function in GBM patients. We systematically analyzed and describe a large population of CD8+CD28- T cells in both the blood and tumor-infiltrating lymphocytes of GBM patients. We found that phenotypically these CD8+CD28- T cells represent a distinct population compared with exhausted T cells. Comparative transcriptomic and pathway analysis of CD8+CD28- T cell populations in GBM patients revealed that tumor microenvironment might be influencing several immune related pathways and thus further exaggerating the age associated immune dysfunction in this patient population.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aging / blood
  • Aging / immunology*
  • Brain Neoplasms / blood
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / immunology
  • Brain Neoplasms / pathology
  • CD28 Antigens / analysis
  • CD28 Antigens / immunology
  • CD28 Antigens / metabolism
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cellular Senescence / immunology
  • Drug Resistance, Neoplasm
  • Female
  • Glioblastoma / blood
  • Glioblastoma / drug therapy*
  • Glioblastoma / immunology
  • Glioblastoma / pathology
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology*
  • Immune Checkpoint Inhibitors / therapeutic use
  • Immunophenotyping
  • Lymphocyte Activation
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Male
  • Middle Aged
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology
  • Young Adult

Substances

  • CD28 Antigens
  • Immune Checkpoint Inhibitors