Basher et al. showed that B10G5, an antibody able to clear soluble human NKG2D ligand (sMIC), synergized with anti-PD-L1. Co-therapy inhibited growth of sMIC+PD-L1+ melanoma to promote survival in syngeneic sMIC+ transgenic host mice; increased numbers of activated/effector-memory, antigen-specific NKG2D+CD8+ T cells and of NK cells with elevated NKG2D and IL-2Rα expression in draining lymph nodes and spleen; and inhibited tumor angiogenesis. B10G5 reversed sMIC-induced anti-survival and anti-proliferative gene expression patterns in NK cells to enable anti-PD-L1 effects. sMIC/MIC is highly expressed in metastatic human melanoma.
Contributed by Paula Hochman
BACKGROUND: Melanoma patients who have detectable serum soluble NKG2D ligands either at the baseline or post-treatment of PD1/PDL1 blockade exhibit poor overall survival. Among families of soluble human NKG2D ligands, the soluble human MHC I chain-related molecule (sMIC) was found to be elevated in melanoma patients and mostly associated with poor response to PD1/PDL1 blockade therapy. METHODS: In this study, we aim to investigate whether co-targeting tumor-released sMIC enhances the therapeutic outcome of PD1/PDL1 blockade therapy for melanoma. We implanted sMIC-expressing B16F10 melanoma tumors into syngeneic host and evaluated therapeutic efficacy of anti-sMIC antibody and anti-PDL1 antibody combination therapy in comparison with monotherapy. We analyzed associated effector mechanism. We also assessed sMIC/MIC prevalence in metastatic human melanoma tumors. RESULTS: We found that the combination therapy of the anti-PDL1 antibody with an antibody targeting sMIC significantly improved animal survival as compared to monotherapies and that the effect of combination therapy depends significantly on NK cells. We show that combination therapy significantly increased IL-2Ralpha (CD25) on NK cells which sensitizes NK cells to low dose IL-2 for survival. We demonstrate that sMIC negatively reprograms gene expression related to NK cell homeostatic survival and proliferation and that antibody clearing sMIC reverses the effect of sMIC and reprograms NK cell for survival. We further show that sMIC/MIC is abundantly present in metastatic human melanoma tumors. CONCLUSIONS: Our findings provide a pre-clinical proof-of-concept and a new mechanistic understanding to underscore the significance of antibody targeting sMIC to improve therapeutic efficacy of anti-PD1/PDL1 antibody for MIC/sMIC(+) metastatic melanoma patients.
Author Info: (1) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA. Current address: Department of Medicine, Miller School of Medicine,
Author Info: (1) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA. Current address: Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA. (2) Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. Driskill Graduate Program in Life Science, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. (3) Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. (4) Driskill Graduate Program in Life Science, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. (5) Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. (6) Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. (7) Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, 60628, USA. (8) Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. jennifer.wu@northwestern.edu. Driskill Graduate Program in Life Science, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. jennifer.wu@northwestern.edu. Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. jennifer.wu@northwestern.edu.
