The human tumor-derived soluble NKG2D ligand, the MHC I-chain related molecule (sMIC), is highly immune suppressive in cancer patients and correlates with poor prognosis. However, the therapeutic effect of targeting sMIC has not been determined, due to the limitation that mice do not express homologs of human MIC. With a clinically relevant transgenic mouse models, we aimed to determine the therapeutic efficacy of a non-blocking sMIC-neutralizing anti-MIC mAb antibody. Treatment of the engineered MIC-expressing “humanized” TRAMP/MIC bi-transgenic mice at advanced disease stages with a sMIC-neutralizing non-blocking mAb effectively induced regression of primary tumors and eliminated metastasis without inducing systemic toxicity. The therapeutic effect is conferred by revamping endogenous anti-tumor immune responses, exemplified by restoring NK cell homeostasis and function, enhancing susceptibility of MIC+-tumor cells to NK cell killing, reviving and sustaining antigen-specific CD8 T cell responses, augmenting CD4 T cells to Th1 responses, priming dendritic cells for antigen presentation, and remodeling tumor microenvironment to be more immune reactive. With a transplantable syngeneic sMIC-expressing B16 melanoma model, we also demonstrated that therapy with the sMIC-neutralizing mAb significantly enhanced the anti-tumor responses of adoptively transferred antigen-specific CD8 and CD4 T cells. We conclude that therapy with a sMIC-neutralizing non-blocking anti-MIC mAb can effectuate anti-tumor immune responses against advanced MIC+ tumors. Our study provided strong rationale for translating sMIC-neutralizing therapeutic mAb into clinics, either alone or in combination with current ongoing standard immunotherapies.
Citation Format: Jennifer Wu. Therapy with a non-blocking monoclonal antibody targeting soluble NKG2D ligand MIC revamps endogenous innate and adaptive anti-tumor responses and eliminates primary and metastatic tumors. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A053.
- ©2016 American Association for Cancer Research.