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

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.