OX40 enhances T cell immune response to PD-1 blockade therapy in non-small cell lung cancer.

Immune-checkpoint blockade is widely studied for cancer therapy. Although the co-inhibitory receptor Programmed death-1(PD-1) blockade benefits some non-small cell lung cancer (NSCLC) patients, a large portion of NSCLC patients still fail to respond to this immunotherapy, and the underlying mechanism is unclear. Thus, a synergistic therapy to enhance the effect of PD-1 is urgently needed to improve the poor outcome of NSCLC patients. Here, we demonstrated that effector memory T cells were increased and T cell response became stronger in PD-1 immunotherapy responders (n = 20) but not in non-responders (n = 10). The expression of co-stimulatory receptor OX40 was upregulated on T cells following PD-1 immunotherapy and was positively associated with the percentage of PD-1+T cells and the responsiveness of T cells. Combination treatment of antagonistic anti-PD-1 and agonistic anti-OX40 antibodies (Abs) promoted the proliferation and cytokines production of T cells from PBMCs of non-responders ex vivo. Consistently, anti-PD-1 and anti-OX40 therapy synergistically augmented T cell response in an in vivo mouse lung cancer model. Our study confirmed the antitumor effects of anti-PD-1/OX40 combination in lung cancer patients as well as in the murine lung cancer model, and the results provide a rationale for clinical trials evaluating the therapeutic effect of this combination of antibodies for NSCLC immunotherapy.

CD103 Promotes the Pro-inflammatory Response of Gastric Resident CD4+ T Cell in Helicobacter pylori-Positive Gastritis.

CD103 is considered as a surface marker for the resident immune cells. However, little is known about the intrinsic function of CD103 in infection and inflammation. In this study, we found that CD103 was highly expressed in CD4+T cells of the gastric mucosa from patients with H. pylori-positive gastritis. Mucosal resident CD103+CD4+T cells exhibited an increase in the CD45RO+CCR7- effector memory phenotype and high expression of the chemokine receptors CXCR3 and CCR9 compared with those in CD103-CD4+T cells. An In vitro coculture study demonstrated that H. pylori-specific antigen CagA/VacA-primed dendritic cells (DCs) induced proliferation and IFN-γ, TNF as well as IL-17 production by CD103+CD4+T cells from patients with H. pylori-positive gastritis, while blocking CD103 with a neutralizing antibody reduced proliferation and IFN-γ, TNF, and IL-17 production by CD103+CD4+T cells cocultured with DCs. Moreover, immunoprecipitation revealed that CD103 interacted with TCR α/ß and CD3ζ, and activation of CD103 enhanced the phosphorylation of ZAP70 induced by the TCR signal. Finally, increased T-bet and Blimp1 levels were also observed in CD103+CD4+T cells, and activating CD103 increased T-bet and Blimp1 expression in CD4+T cells. Our results explored the intrinsic function of CD103 in gastric T cells from patients with H. pylori-positive gastritis, which may provide a therapeutic target for the treatment of gastritis.