Expression of KLRG1 and CD127 defines distinct CD8(+) subsets that differentially impact patient outcome in follicular lymphoma

BACKGROUND: CD8(+) T-lymphocyte subsets defined by killer lectin-like receptor G1 (KLRG1) and CD127 expression have been reported to have an important role in infection, but their role in the setting of lymphoid malignancies, specifically follicular lymphoma (FL), has not been studied. METHODS: To characterize the phenotype of KLRG1/CD127-defined CD8(+) subsets, surface and intracellular markers were measured by flow cytometry and Cytometry by time of flight (CyTOF), and the transcriptional profile of these cells was determined by CITE-Seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing). The functional capacity of each subset was determined, as was their impact on overall survival (OS) and event-free survival (EFS) of patients with FL. RESULTS: We found that intratumoral CD8(+) cells in FL are skewed toward effector cell subsets, particularly KLRG(+)CD127(-) and KLRG1(-)CD127(-) cells over memory cell subsets, such as KLRG1(-)CD127(+) and KLRG1(+)CD127(+) cells. While effector subsets exhibited increased capacity to produce cytokines/granules when compared with memory subsets, their proliferative capacity and viability were found to be substantially inferior. Clinically, a skewed distribution of intratumoral CD8(+) T cells favoring effector subtypes was associated with an inferior outcome in patients with FL. Increased numbers of CD127(+)KLRG1(-) and CD127(+)KLRG1(+) were significantly associated with a favorable OS and EFS, while CD127(-)KLRG1(-) correlated with a poor EFS and OS in patients with FL. Furthermore, we demonstrated that interleukin (IL)-15 promotes CD127(-)KLRG1(+) cell development in the presence of dendritic cells via a phosphoinositide 3-kinase (PI3K)-dependent mechanism, and treatment of CD8(+) T cells with a PI3K inhibitor downregulated the transcription factors responsible for CD127(-)KLRG1(+) differentiation. CONCLUSIONS: Taken together, these results reveal not only a biological and prognostic role for KLRG1/CD127-defined CD8(+) subsets in FL but also a potential role for PI3K inhibitors to manipulate the differentiation of CD8(+) T cells, thereby promoting a more effective antitumor immune response.