Zhao et al. demonstrated that radiation therapy (RT) induced TIGIT expression on tumor-infiltrating lymphocytes in patients with ESCC and in syngeneic tumor models. Anti-TIGIT therapy enhanced the antitumor effect of RT and prolonged survival in solid tumor models. The combination treatment increased tumor-infiltrating CD8+ T cells expressing TNFα and IFNγ, and CD103+ DCs. The CD103+ DCs were necessary for combination therapy-mediated effector CD8+ T cell recruitment and activation within the TME. Flt3 ligand injection expanded CD103+ DCs in the tumors and enhanced tumor control in the RT plus anti-TIGIT combination.
Contributed by Shishir Pant
ABSTRACT: Blockade of the T cell immunoreceptor with the immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) can enhance innate and adaptive tumor immunity and radiotherapy (RT) can enhance anti-tumor immunity. However, our data suggest that TIGIT-mediated immune suppression may be an impediment to such goals. Herein, we report on the synergistic effects of RT combined with anti-TIGIT therapy and the mechanism of their interaction. Treatment efficacy was assessed by measuring primary and secondary tumor growth, survival, and immune memory capacity. The function of CD103 + dendritic cells (DCs) under the combined treatment was assessed in wild-type and BATF3-deficient (BATF3-/-) mice. FMS-like tyrosine kinase 3 ligand (Flt3L) was used to confirm the role of CD103 + DCs in RT combined with anti-TIGIT therapy. TIGIT was upregulated in immune cells following RT in both esophageal squamous cell carcinoma patients and mouse models. Administration of the anti-TIGIT antibody enhanced the efficacy of RT through a CD8 + T cell-dependent mechanism. It was observed that RT and the anti-TIGIT antibody synergistically enhanced the accumulation of tumor-infiltrating DCs, which activated CD8 + T cells. The efficacy of the combination therapy was negated in the BATF3-/- mouse model. CD103 + DCs were required to promote the anti-tumor effects of combination therapy. Additionally, Flt3L therapy enhanced tumor response to RT combined with TIGIT blockade. Our study demonstrated TIGIT blockade can synergistically enhance anti-tumor T cell responses to RT via CD8 + T cells (dependent on CD103 + DCs), suggesting the clinical potential of targeting the TIGIT pathway and expanding CD103 + DCs in RT.
Author Info: (1) Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. Department o
Author Info: (1) Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. Department of Radiation Oncology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China. (2) Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. (3) Department of Radiology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. Department of Radiology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China. (4) Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. Cheeloo College of Medicine, Shandong University, Jinan, China. (5) Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China. devin813@163.com. (6) Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. mengxiangjiao@126.com.
