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

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.

Senescent Tumor Cells in the Peritoneal Carcinomatosis Drive Immunosenescence in the Tumor Microenvironment

“…Senescent tumor cells that induce senescence in immune TME cells via secretion of SASP factors seem represent a more widespread phenomenon in aggressive tumors that are resistant to immune checkpoint blockade. In the most aggressive brain cancer, the Glioblastoma multiforme (GBM), patients displayed not only senescent tumor cells but also senescent immune cells in the tumor microenvironment and systemically in peripheral blood (27)(28)(29). In this context, a recent study by Puca et al could show that treatment of senescent glioblastoma U87-MG cells and senescent T-cells derived from peripheral blood of GBM patients with the senolytic drug longevity-associated variant (LAV) of the bactericidal/permeability-increasing foldcontaining family B member 4 (LAV-BPIFB4) reduced the senescent phenotype in both U87-MG cells and patient-derived PBMCs (29).…”

“…Senescent tumor cells that induce senescence in immune TME cells via secretion of SASP factors seem represent a more widespread phenomenon in aggressive tumors that are resistant to immune checkpoint blockade. In the most aggressive brain cancer, the Glioblastoma multiforme (GBM), patients displayed not only senescent tumor cells but also senescent immune cells in the tumor microenvironment and systemically in peripheral blood ( 27 – 29 ). In this context, a recent study by Puca et al.…”

“…Induction of immunosenescence by senescent tumor cells is not limited to PC but could be a broader escape mechanism of aggressive tumors that are resistant to checkpoint inhibitor blockade. within the most aggressive malignant primary brain tumor, the Glioblastoma multiforme (GBM), several studies could show that patients with GBM have significantly more senescent cancer cells and more senescent T cells not only in the TME but also systemically in the peripheral blood compared with healthy age matched controls ( 27 – 29 ). Our results provide insights into a unique metastatic tumor site and shed new light on the mechanistics of senescence and immunosenescence within PC.…”

CD8+ T Cell Senescence: Lights and Shadows in Viral Infections, Autoimmune Disorders and Cancer

“…Likewise, in Acute Myeloid Leukemia (AML) patients, the gene expression profile of peripheral CD8 + T cells showed a premature senescent phenotype, characterized by the expression of CD57, and an exhausted state, supported by the upregulation of PD-1 and CTLA-4, which was remarkably enhanced after chemotherapy [ 100 ]. Notably, an enrichment of CD28 − CD8 + T cells, besides going along with T cell immunosenescence, was also found in patients with glioblastoma (GBM) [ 101 ]. Indeed, a pro-tumoral effect of this subset is suggested by the worse prognosis observed in elderly GBM patients [ 102 , 103 ].…”

“…In fact, these cells lack the main ICI targets, PD-1 and T-cell Immunoglobulin Mucin (TIM)-3, thus explaining the failure of ICI treatment. Moreover, all senescent features appeared exacerbated in GBM by comparison to sex- and age-matched healthy subjects [ 101 ].…”