In response to oncogenic stress, human epithelial cells express the MHC-I chain related molecule, MIC, to alert the immune system by engaging the activation immune receptor NKG2D expressed on nature killer (NK) cells and effector T cells. However, human cancer cells broadly adopt a strategy to evade NKG2D-mediated immunity by shedding surface MIC to produce soluble MIC (sMIC). It has been well demonstrated that sMIC poses global insults to the immune system by down-regulating NKG2D expression on NK and effect T cells. Elevated serum levels of sMIC correlates with disease stages in many cancer types. These clinical observations suggested that sMIC may be a cancer therapeutic target. However, due to the major obstacle that no human MIC homolog is present in rodents, the concept of targeting sMIC cannot be tested pre-clinically until now. To overcome this limitation, we have generated and characterized a humanized MIC/TRAMP bi- transgenic mouse model in which human MIC and the oncogene concurrently expressed in a specific tissue, the prostate. The TRAMP/MIC mice closely resemble human cancer patients pathologically and immunologically and thus provide us with a valid preclinical tool to evaluate whether sMIC is a therapeutic target. With the TRAMP/MIC mouse model, we also uncovered the novel sMIC immune suppressive effect whereby sMIC perturbs NK cell maintenance in tumor host. This immune suppressive effect of sMIC is also found in cancer patients. We further found that sMIC stimulation induces PD-1 expression on NK cells and that ligation of PD-1 by its ligands impairs NK cell viability in vitro. Based on these preliminary observations, we hypothesize that upregulation of PD-1 expression contributes significantly to sMIC-mediated perturbation of NK cell maintenance in cancer patients. Importantly, we have developed a sMIC-neutralizing monoclonal antibody which we have shown to effectively revive host NK cells and potentiate antigen-specific CD8 T cell anti-tumor responses. Based on these findings, we further hypothesize that a combinatory therapy of targeting sMIC and PD-1 blockade can generate synergistic anti-tumor effect through releasing immune check-point brake and simultaneously re-setting the NK cell and T cell immunity the engine to concurrently revamp endogenous anti-tumor responses. We plan to test our hypothesis with three Specific Aims: 1) To determine the mechanisms whereby sMIC induces PD-1 expression on NK cells; 2) To delineate the impact of PD-1 signaling on NK cell homeostasis in sMIC+ tumor host and the underlying molecular link; 3) To evaluate the combinatory therapeutic efficacy of PD-1 blockade and targeting sMIC in MIC+ tumor host. Our proposed study will not only uncover novel understandings of NKG2D and NK cell biology, but also will have significant and potentially immediate clinical implications in translating NKG2D tumor immunity into clinical practices.
We propose to investigate the mechanisms whereby soluble NKG2D ligand sMIC impairs NK cell homeostasis maintenance in tumor hosts. We also propose to evaluate a therapy of targeting sMIC combined with PD-1 blockade for human epithelial originated cancers. Our proposed study not only will have significant impact on improving cancer immunotherapy, but also will shed significant light on autoimmunity and transplant biology.
|Wallace, Kristin; Lewin, David N; Sun, Shaoli et al. (2018) Tumor-Infiltrating Lymphocytes and Colorectal Cancer Survival in African American and Caucasian Patients. Cancer Epidemiol Biomarkers Prev 27:755-761|
|Dhar, Payal; Wu, Jennifer D (2018) NKG2D and its ligands in cancer. Curr Opin Immunol 51:55-61|
|Zhang, Jingyu; Liu, Dai; Li, Guangfu et al. (2017) Antibody-mediated neutralization of soluble MIC significantly enhances CTLA4 blockade therapy. Sci Adv 3:e1602133|
|Liu, Gang; Zhang, Jinyu; Frey, Lewis et al. (2017) Prostate-specific IL-6 transgene autonomously induce prostate neoplasm through amplifying inflammation in the prostate and peri-prostatic adipose tissue. J Hematol Oncol 10:14|
|Metelli, Alessandra; Wu, Bill X; Fugle, Caroline W et al. (2016) Surface Expression of TGF? Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer. Cancer Res 76:7106-7117|
|Liu, Qian; Li, Anping; Tian, Yijun et al. (2016) The CXCL8-CXCR1/2 pathways in cancer. Cytokine Growth Factor Rev 31:61-71|