title: NK cells and CD8+ T cells cooperate to improve therapeutic responses in melanoma treated with interleukin-2 (IL-2) and CTLA-4 blockade.
abstract: BACKGROUND
  Melanoma is one of the few types of cancer with an increasing annual incidence. While a number of immunotherapies for melanoma have been associated with significant clinical benefit, including high-dose IL-2 and cytotoxic T lymphocyte antigen 4 (CTLA-4) blockade, clinical response to either of these single agents has been limited to 11-20% of treated patients. Therefore, in this study, we sought to test the hypothesis that the combination of IL-2 and CTLA-4 blockade could mediate a more profound therapeutic response.
  
  
  METHODS
  Here, B6 mice were challenged with poorly immunogenic B16 melanoma on day 0, and treated with CTLA-4 blocking antibody (100 μg/mouse) on days 3, 6, and 9, and IL-2 (100,000 units) twice daily on days 4-8, or both.
  
  
  RESULTS
  A highly significant synergistic effect that delayed tumor growth and prolonged survival was demonstrated with the combination immunotherapy compared to either monotherapy alone. The therapeutic effect of combination immunotherapy was dependent on both CD8+ T and NK cells and co-depletion of these subsets (but not either one alone) abrogated the therapeutic effect. CTLA-4 blockade increased immune cell infiltration (including CD8+ T cells and NK cells) in the tumor and IL-2 reduced the proportion of highly differentiated/exhausted tumor-infiltrating NK cells.
  
  
  CONCLUSIONS
  These results have implications for the design of clinical trials in patients with metastatic melanoma and provide new insights into how the immune system may be mediating anti-tumor activity with combination IL-2 and CTLA-4 blockade in melanoma.
authors.affiliation: Rutgers Cancer Institute of New Jersey, 195 Little Albany Street Room 2007, New Brunswick, NJ 08901 USA.|Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Kohlhapp
authors.affiliation: Department of General Surgery, Rush University Medical Center, Chicago, IL 60612 USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Broucek
authors.affiliation: Department of General Surgery, Rush University Medical Center, Chicago, IL 60612 USA.
authors.forename: Tasha
authors.initials: T
authors.lastname: Hughes
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA.
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Huelsmann
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA.
authors.forename: Jevgenijs
authors.initials: J
authors.lastname: Lusciks
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA.
authors.forename: Janet P
authors.initials: JP
authors.lastname: Zayas
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA.
authors.forename: Hubert
authors.initials: H
authors.lastname: Dolubizno
authors.affiliation: Department of General Surgery, Rush University Medical Center, Chicago, IL 60612 USA.
authors.forename: Vidyaratna A
authors.initials: VA
authors.lastname: Fleetwood
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA.
authors.forename: Alisa
authors.initials: A
authors.lastname: Grin
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA.
authors.forename: Graham E
authors.initials: GE
authors.lastname: Hill
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Poshepny
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA.|Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612 USA.
authors.forename: Arman
authors.initials: A
authors.lastname: Nabatiyan
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA.|Department of General Surgery, Rush University Medical Center, Chicago, IL 60612 USA.
authors.forename: Carl E
authors.initials: CE
authors.lastname: Ruby
authors.affiliation: Department of Pharmacology & Toxicology and Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555 USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Snook
authors.affiliation: Department of Pharmacology & Toxicology and Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555 USA.
authors.forename: Jai S
authors.initials: JS
authors.lastname: Rudra
authors.affiliation: Department of Microbiology and Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455 USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Schenkel
authors.affiliation: Department of Microbiology and Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455 USA.
authors.forename: David
authors.initials: D
authors.lastname: Masopust
authors.affiliation: Rutgers Cancer Institute of New Jersey, 195 Little Albany Street Room 2007, New Brunswick, NJ 08901 USA.|Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA.|Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612 USA.|Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903 USA.
authors.forename: Andrew
authors.identifier: 0000-0001-8844-6493
authors.initials: A
authors.lastname: Zloza
authors.affiliation: Rutgers Cancer Institute of New Jersey, 195 Little Albany Street Room 2007, New Brunswick, NJ 08901 USA.|Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903 USA.
authors.forename: Howard L
authors.initials: HL
authors.lastname: Kaufman
keywords: CD8+ T cells; CTLA-4; Immunotherapy; Interleukin-2; NK cells