Aging as well as Tumor Related Immune Senescence Imposes a Strong Barrier to Success of Immunotherapy in Glioblastoma
Kaleigh Fetcko, Mahua Dey, Yunlong Liu, Mario Henriquez, Sharlé Newman, Jae Hyun Kwon, Leo Song, Tamara Jones, Hiromi Tanaka, Jun Wan, Wei Huff
Introduction: Glioblastoma is a disease of older adults. Aging affects all immune cells including CD8+ T-cells, the corner stone of all immunotherapy. CD8+ T-cell senescence, as represented by CD28 downregulation is a normal part of aging and is also observed in many cancers, however their function in glioblastoma remains unknown.
Objective: To investigate the role of aging as well as tumor associated CD8+ T-cell senescence in glioblastoma.
Methods: To characterize CD8+ T-cell senescence, CD8+CD28- and CD8+CD28+ T-cells were isolated from tumor and blood of patients with glioblastoma, blood of age matched control and younger control. All the groups were analyzed for senescence associated markers and intracellular cytokines as well as telomere lengths and RNA-seq was performed to identify differential gene expression.
Results: Our results show the presence of a large population of CD8+CD28- T-cells in both blood and tumor of glioblastoma patients compared to age matched and younger control. CD8+CD28- T-cells represents a distinct population compared to exhausted T-cells and express less CD107a when compared to their CD8+CD28+ counterparts implying compromised cytotoxic abilities. In addition, CD8+CD28- T-cells express less inflammatory/regulatory cytokines, such as IL-4 and IL-10, suggesting altered regulatory functional compared to CD8+CD28+ T-cells. Both aging and tumor associated functional changes in the CD8+CD28- T-cells are telomere-dependent. In terms of overall gene expression, there is significant differential gene expression and specific gene signature in each group.
Conclusions: In this study we for the first time systematically characterize glioblastoma induced CD8+ T-cells senescence and show the effect of aging on the endogenous immune response to glioblastoma.