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Evidence of Interleukin 21 Reduction in Osteosarcoma Patients Due to PD-1/PD-L1-Mediated Suppression of Follicular Helper T Cell Functionality.

Interleukin 21 (IL-21) is crucial for the development of a robust CD8+ T cell response and has been shown to promote antitumor immunity. Despite the fact that osteosarcoma presents significant genetic instability with a high immunogenic potential, the antitumor immune response in osteosarcoma is ineffective. We investigated whether this was due to impaired IL-21 responses. We found that the circulating CD4+ T cells, a major source of IL-21, had reduced capacity to express IL-21 in osteosarcoma patients compared to healthy controls. The IL-21 expression in healthy controls was equally shared between Th17 and follicular helper T (Tfh) cells, while in osteosarcoma patients, the Tfh cells presented a severe reduction in IL-21 secretion capacity as well as in proliferation capacity. To explain this loss of Tfh functionality, we found that Tfh cells expressed the highest level of PD-1 among all CD4+ T cell subsets examined. While PD-1 might be crucial for normal Tfh function in healthy individuals, in patients with programmed death ligand 1 (PD-L1)+ tumor, the PD-1/PD-L1 pathway on Tfh cells might be sabotaged to mediate immunosuppression. Indeed, the IL-21 production by Tfh cells was significantly reduced in the presence of PD-L1+ tumor cells and was rescued by the anti-PD-L1 antibody. In healthy individuals, CXCR5+ Tfh cells could enhance the interferon (IFN)-γ secretion, degranulation, and cytotoxicity of CD8+ T cells, but this function of Tfh cells was lost in osteosarcoma patients. Together, this study demonstrated a dysregulated pathway that should be targeted for future immunotherapies in osteosarcoma.