title: CD8+T cell-specific induction of NKG2D receptor by doxorubicin plus interleukin-12 and its contribution to CD8+T cell accumulation in tumors.
abstract: BACKGROUND
  Increased infiltration of CD8+T cells into tumors has a positive impact on survival. Our previous study showed that doxorubicin (Dox) plus interleukin-12 (IL-12) boosted the accumulation of CD8+T cells in tumors and had a greater antitumor effect than did either agent alone. The purpose of this study was to determine the impact of NKG2D expression on CD8+T cell infiltration and antitumor efficacy.
  
  
  METHODS
  Tumor-bearing mice were administered Dox, IL-12 plasmid DNA, or both via intraperitoneal injection or intramuscular electroporation. The induction of NKG2D on CD8+T cells and other lymphocytes was analyzed via flow cytometry, and NKG2D-positive CD8+T cell-specific localization in tumors was determined by using immunofluorescence staining in various types of immune cell-depleted mice.
  
  
  RESULTS
  The combination of Dox plus IL-12 specifically increased expression of NKG2D in CD8+T cells but not in other types of immune cells, including NK cells, which naturally express NKG2D. This induced NKG2D expression in CD8+T cells was associated with increased accumulation of CD8+T cells in murine tumors. Administration of NKG2D-blocking antibody or CD8+T cell-depletion antibody abrogated the NKG2D+CD8+T cell detection in tumors, whereas administration of NK cell-depletion antibody had no effect. Increased NKG2D expression in CD8+T cells was associated with increased antitumor efficacy in vivo.
  
  
  CONCLUSIONS
  We conclude that Dox plus IL-12 induces NKG2D in CD8+T cells in vivo and boosts NKG2D+CD8+T-dependent antitumor immune surveillance. This discovery reveals a novel mechanism for how chemoimmunotherapy synergistically promotes T cell-mediated antitumor immune surveillance.
authors.forename: Jiemiao
authors.initials: J
authors.lastname: Hu
authors.forename: Shiguo
authors.initials: S
authors.lastname: Zhu
authors.forename: Xueqing
authors.initials: X
authors.lastname: Xia
authors.forename: Liangfang
authors.initials: L
authors.lastname: Zhang
authors.forename: Eugenie S
authors.initials: ES
authors.lastname: Kleinerman
authors.affiliation: Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Sli4@mdanderson.org.
authors.forename: Shulin
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015316:Genetic Therapy; D007167:Immunotherapy; D018664:Interleukin-12 / Q000008:administration & dosage / Q000235:genetics; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis / Q000276:immunology*; D010957:Plasmids
chemical_list: C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D018664:Interleukin-12; D004317:Doxorubicin