PD-1 regulates CXCR5⁺ CD4 T cell-mediated proinflammatory functions in non-small cell lung cancer patients

PD-1 inhibitors have been used to revive exhausted T cell responses in non-small cell lung cancer (NSCLC) and other malignancies. CXCR5⁺ T follicular helper (Tfh) cells are characterized by constitutive high PD-1 expression and have been associated with the formation of tertiary lymphoid structures and implicated in antitumor immunity. In this study, we investigated the effect of PD-1 and PD-1 inhibition on CXCR5⁺ CD4 T cells. Data showed that CXCR5⁺ CD4 T cells in both healthy subjects and NSCLC patients presented markedly higher PD-1 expression than CXCR5^- CD4 T cells. Both CXCR5^- and CXCR5⁺ CD4 T cells from NSCLC patients presented higher PD-1 expression than their counterparts in healthy subjects. PD-1⁺ CXCR5⁺ CD4 T cells were functional, could express IL-21, IL-10, and CXCL13 upon stimulation, demonstrated auxiliary effects toward CD8 T cell-mediated IFN-γ production and proliferation, and promoted IgM and IgG production. However, the potency of PD-1⁺ CXCR5⁺ CD4 T cells was lower than the potency of PD-1^- CXCR5⁺ CD4 T cells. PD-1 blocking could significantly enhance the effector functions of PD-1⁺ CXCR5⁺ CD4 T cells. Overall, this study demonstrated that PD-1⁺ CXCR5⁺ CD4 T cells could promote CD8 T cell and B cell inflammation and could be modulated by PD-1 inhibition.