title: Induction of NKG2D Ligands on Solid Tumors Requires Tumor-Specific CD8+T Cells and Histone Acetyltransferases.
abstract: NKG2D-mediated immune surveillance is crucial for inhibiting tumor growth and metastases. Malignant tumor cells often downregulate NKG2D ligands to escape from immune surveillance. High-profile studies have shown that restoring NKG2D ligand expression via genetic engineering inhibits tumor formation and progression. However, no effectivein vivoapproaches are available to restore these ligands across different types of solid tumors because the classic stress signal-dependent induction of this ligandin vitrois transient and has rarely been duplicated in solid tumorsin vivoWe found that coadministration of an immune stimulatory signal (IL12) and chemotherapy (doxorubicin) restored the NKG2D ligand Rae-1 in multiple tumor types, including a human tumor model. The restored expression of NKG2D ligands was associated with tumor cell death and delay of tumor progressionin vivoInduction of tumor-specific NKG2D ligands required the engagement of CD8+T cells and was regulated by the histone acetyltransferases GCN5 and PCAF. The tumor-specific restoration of NKG2D ligands in a variety of tumor models, including a human tumor model, resulted in NKG2D-dependent tumor regression and extended survival time. The elucidation of a CD8+T cell-dependent mechanism suggests that activated NKG2D+CD8+T-cell therapy alone may be able to restore the NKG2D ligand in tumors.Cancer Immunol Res; 5(4); 300-11. ©2017 AACR.
authors.affiliation: Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jiemiao
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chantale
authors.initials: C
authors.lastname: Bernatchez
authors.affiliation: Department of NanoEngineering, University of California, San Diego, California.
authors.forename: Liangfang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Xia
authors.affiliation: Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Eugenie S
authors.initials: ES
authors.lastname: Kleinerman
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Center of Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.affiliation: Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. Sli4@mdanderson.org.
authors.forename: Shulin
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034521:Nuclear Matrix-Associated Proteins; D029543:Nucleocytoplasmic Transport Proteins; C490522:RAE1 protein, human; D018664:Interleukin-12; D004317:Doxorubicin; D051548:Histone Acetyltransferases