Nonblocking Monoclonal Antibody Targeting Soluble MIC Revamps Endogenous Innate and Adaptive Antitumor Responses and Eliminates Primary and Metastatic Tumors

Purpose: The human tumor-derived soluble 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. This study is to evaluate the therapeutic effect of a monoclonal antibody (mAb) targeting sMIC in a clinically relevant transgenic animal model. Experimental Design: We treated the engineered MIC-expressing humanized TRAMP/MIC bitransgenic mice at advanced disease stages with a sMIC-neutralizing nonblocking anti-MIC mAb and assessed the therapeutic efficacy and associated mechanisms. Results: A sMIC-neutralizing nonblocking anti-MICmAb effectively induced regression of primary tumors and eliminated metastasis without inducing systemic toxicity. The therapeutic effect is conferred by revamping endogenous antitumor immune responses, exemplified by restoring natural killer (NK) cell homeostasis and function, enhancing susceptibility of MIC+-tumor cells to NK cell killing, reviving and sustaining antigenspecific 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. Conclusions: Therapy with a sMIC-neutralizing nonblocking anti-MICmAbcan effectuate antitumor 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. (C)2015 AACR.