Huff, Wei X.Bam, MarpeShireman, Jack M.Kwon, Jae HyunSong, LeoNewman, SharléCohen-Gadol, Aaron A.Shapiro, ScottJones, TamaraFulton, KelseyLiu, ShengTanaka, HiromiLiu, YunlongWan, JunDey, Mahua2023-04-062023-04-062021-06-08Huff WX, Bam M, Shireman JM, et al. Aging- and Tumor-Mediated Increase in CD8+CD28- T Cells Might Impose a Strong Barrier to Success of Immunotherapy in Glioblastoma. Immunohorizons. 2021;5(6):395-409. Published 2021 Jun 8. doi:10.4049/immunohorizons.2100008https://hdl.handle.net/1805/32258Clinical 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 co-receptors, 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 antigen 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 to 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.en-USPublisher PolicyImmune dysfunctionCD8+CD28− T cellsGlioblastomaImmunotherapyTelomereArticle