Human CXCR5+PD-1+ CD8 T cells in healthy individuals and patients with hematologic malignancies

Immune checkpoint blockade (ICB) has revolutionized cancer therapy, but varying response rates illustrate the need for biomarkers of response. Studies in mice have identified a subset of CD8 T cells that is essential for response to PD-1 ICB. These CD8 T cells co-express CXCR5, PD-1 and Tcf1, and provide effector T cells upon PD-1 ICB. It is unknown whether similar T cells play a role in PD-1 ICB in humans. We studied human peripheral blood and lymph nodes (LNs) for the frequency, phenotype, and functionality of CXCR5⁺PD-1⁺ CD8 T cells. We find that CXCR5⁺PD-1⁺ CD8 T cells are memory-like cells, express Tcf1, and lack expression of effector molecules. CXCR5⁺PD-1⁺ CD8 T cells produce cytokines upon stimulation, but have limited proliferative capacity. We studied patients with hematologic malignancies with varying response rates to PD-1 ICB. Specifically in chronic lymphocytic leukemia, in which PD-1 ICB does not induce clinical responses, CXCR5⁺PD-1⁺ CD8 T cells show loss of the memory phenotype and increased effector differentiation. In conclusion, we identified CXCR5⁺PD-1⁺ CD8 T cells in human peripheral blood and LN, which could play a similar role during PD-1 ICB. Future studies should analyze CXCR5⁺PD-1⁺ CD8 T cells during PD-1 ICB and their importance for therapeutic response.