Induction of Innate Immune Visibility of Neuroendocrine Tumors Potentiates Immune Responses and Tumor Rejection

Abstract

Abstract Natural killer (NK) cells serve as an important role in suppressing tumor growth by directly attacking malignant cells. These cells recognize the tumor cells through moleclar patterns associated with oncogenic transformation. NKG2D ligands (NKG2DLs) are one of these markers present on tumor cells which can activate NK cells and T cells by interacting with NKG2D receptors on these lymphocytes. Majority of tumors express NKG2DLs. Interestingly, tumors carrying neuroendocrine features such as small cell lung cancer (SCLC) and neuroblastoma express very low level of ligands for NK cell activating receptor NKG2D (MICA, MICB, ULBP1, ULBP2, ULBP3), which may help them escape from innate immune surveillance. Further characterization of SCLC immune environment showed reduced antigen presentation, reduced infiltration of total immune cells specifically NK cells, as compared to NSCLC, a more immunogenic tumor. Transcriptional inducers of NKG2DLs did not induce NKG2DL in SCLCs due to hypo-acetylation of MICA/B region. Histone deacetylase (HDAC) inhibitors were able to induce NKG2DL on tumor cell surface. Restoring NKG2DL in preclinical SCLC and neuroblastoma models either by ectopic expression or HDAC inhibitors stimulated direct NK cell killing in co-culture assays. NKG2DL stimulation also caused potentiation of antibody directed therapies such as CD3-EpCAM in neuroendocrine tumors. In vivo studies showed suppressed tumor growth and metastasis in an NK and CD8 T cell dependent manner when NKG2DLs are stimulated. We conclude that: restoring innate immune visibility can target neuroendocrine tumors to both innate and adaptive immune cytotoxicity.