Bae et al. demonstrate that in mice with tumors resistant to anti-PD-1, treatment with antigen-presenting cells (APCs: B cells and monocytes) loaded with α-galactosylceramide leads to improved tumor control via IL-2 production by invariant natural killer T cells and IL-12 production by CD11c+ dendritic cells and CD11b+ myeloid cells. The two cytokines restore function to exhausted CD8+ T cells and reduce their PD-1 expression, leading to delayed tumor growth. Addition of anti-PD-1 synergizes to induce complete response and improve survival in mice.

PD-1-based cancer immunotherapy is a successful example of immune checkpoint blockade that provides long-term durable therapeutic effects in cancer patients across a wide spectrum of cancer types. Accumulating evidence suggests that anti-PD-1 therapy enhances anti-tumor immunity by reversing the function of exhausted T cells in the tumor environment. However, the responsiveness rate of cancer patients to anti-PD-1 therapy remains low, providing an urgent need for optimization and improvement. In this study, we designed an anti-PD-1-resistant mouse tumor model and showed that unresponsiveness to anti-PD-1 is associated with a gradual increase in CD8 T cell exhaustion. We also found that invariant natural killer T (iNKT) cell stimulation by the synthetic ligand alpha-galactosylceramide (alphaGC) can enhance the anti-tumor effect in anti-PD-1-resistant tumors by restoring the effector function of tumor antigen-specific exhausted CD8 T cells. IL-2 and IL-12 were among the cytokines produced by alphaGC stimulation critical for reinvigorating exhausted CD8 T cells in tumor-bearing mice and cancer patients. Furthermore, we observed a synergistic increase in the anti-tumor effect between alphaGC-loaded antigen-presenting cells (APC) and PD-1 blockade in a therapeutic murine tumor model. Our study suggests NKT cell stimulation as a promising therapeutic strategy for the treatment of anti-PD-1-resistant cancer patients.

Author Info: (1) Laboratory of Immunology, College of Pharmacy/Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University. (2) Department

Author Info: (1) Laboratory of Immunology, College of Pharmacy/Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University. (2) Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University. (3) Research Institute of Pharmaceutical Sciences, Seoul National University. (4) Seoul National University. (5) Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University. (6) Laboratory of Immunology, College of Pharmacy/Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University. (7) Laboratory of Immunology, College of Pharmacy/Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University. (8) Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University. (9) Seoul National University. (10) Surgery, Yonsei University College of Medicine. (11) Yonsei University College of Medicine. (12) Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine. (13) Laboratory of Immunology, College of Pharmacy/Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University cykang@snu.ac.kr.

Less