Using models of malignant mesothelioma in immunocompetent mice, Li et al. found that AMD3100 (a CXCR4 antagonist) enhances the antitumor efficacy of the fusion protein vaccine VIC-008 and improves survival. VIC-008 augmented tumor antigen-specific CD8+ T cell responses and facilitated tumor infiltration by lymphocytes, but was associated with increased PD-1 expression. AMD3100 reduced PD-1 expression in CD8+ T cells, reduced tumor infiltration by Tregs, and converted Tregs into helper-like cells.
AMD3100 (plerixafor), a CXCR4 antagonist, has been demonstrated to suppress tumor growth and modulate intratumoral T-cell trafficking. However, the effect of AMD3100 on immunomodulation remains elusive. Here, we explored immunomodulation and antitumor efficacy of AMD3100 in combination with a previously developed mesothelin-targeted, immune-activating fusion protein, VIC-008, in two syngeneic, orthotopic models of malignant mesothelioma (MM) in immunocompetent mice. We showed that combination therapy significantly suppressed tumor growth and prolonged animal survival in two mouse models. Tumor control and survival benefit were associated with enhanced antitumor immunity. VIC-008 augmented mesothelin-specific CD8+ T-cell responses in the spleen and lymph nodes and facilitated intratumoral lymphocytic infiltration. However, VIC-008 treatment was associated with increased PD-1 expression on intratumoral CD8+ T cells, likely due to high CXCL12 in the tumor microenvironment. AMD3100 alone and in combination with VIC-008 modulated immunosuppression in tumors and the immune system through suppression of PD-1 expression on CD8+ T cells and conversion of regulatory T cells (Tregs) into CD4+CD25-Foxp3+IL2+CD40L+ helper-like cells. In mechanistic studies, we demonstrated that AMD3100-driven Treg reprogramming required TCR activation and was associated with loss of PTEN due to oxidative inactivation. The combination of VIC-008 augmentation of tumor-specific CD8+ T-cell responses with AMD3100 abrogation of immunosuppression conferred significant benefits for tumor control and animal survival. These data provide new mechanistic insight into AMD3100-mediated immunomodulation and highlight the enhanced antitumor effect of AMD3100 in combination with a tumor antigen-targeted therapy in mouse MM, which could be clinically relevant to patients with this difficult to treat disease.
Author Info: (1) Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School. (2) Vaccine and Immunotherapy Center, Department of Medicin
Author Info: (1) Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School. (2) Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School. (3) Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School. (4) Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School. (5) Second Military Medical University, National Key Laboratory of Medical Immunology. (6) Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School. (7) Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School. (8) Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School. (9) Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School. (10) Psychiatry, McLean Hospital. (11) Department of Orthopaedics, Institute of Orthopaedic Research, Second Affiliated Hospital of Zhejiang University School of Medicine. (12) Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School. (13) Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School. (14) Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School. (15) Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School huabiao.chen@mgh.harvard.edu. (16) Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School.
