title: Cancer resistance of SR/CR mice in the genetic knockout backgrounds of leukocyte effector mechanisms: determinations for functional requirements.
abstract: BACKGROUND
  Spontaneous Regression/Complete Resistant (SR/CR) mice are a colony of cancer-resistant mice that can detect and rapidly destroy malignant cells with innate cellular immunity, predominately mediated by granulocytes. Our previous studies suggest that several effector mechanisms, such as perforin, granzymes, or complements, may be involved in the killing of cancer cells. However, none of these effector mechanisms is known as critical for granulocytes. Additionally, it is unclear which effector mechanisms are required for the cancer killing activity of specific leukocyte populations and the survival of SR/CR mice against the challenges of lethal cancer cells. We hypothesized that if any of these effector mechanisms was required for the resistance to cancer cells, its functional knockout in SR/CR mice should render them sensitive to cancer challenges. This was tested by cross breeding SR/CR mice into the individual genetic knockout backgrounds of perforin (Prf-/-), superoxide (Cybb-/), or inducible nitric oxide (Nos2-/).
  
  
  METHODS
  SR/CR mice were bred into individual Prf-/-, Cybb-/-, or Nos2-/- genetic backgrounds and then challenged with sarcoma 180 (S180). Their overall survival was compared to controls. The cancer killing efficiency of purified populations of macrophages and neutrophils from these immunodeficient mice was also examined.
  
  
  RESULTS
  When these genetically engineered mice were challenged with cancer cells, the knockout backgrounds of Prf-/-, Cybb-/-, or Nos2-/- did not completely abolish the SR/CR cancer resistant phenotype. However, the Nos2-/- background did appear to weaken the resistance. Incidentally, it was also observed that the male mice in these immunocompromised backgrounds tended to be less cancer-resistant than SR/CR controls.
  
  
  CONCLUSIONS
  Despite the previously known roles of perforin, superoxide or nitric oxide in the effector mechanisms of innate immune responses, these effector mechanisms were not required for cancer-resistance in SR/CR mice. The resistance was functional when any one of these effector mechanisms was completely absent, except some noticeably reduced penetrance, but not abolishment, of the phenotype in the male background in comparison to female background. These results also indicate that some other effector mechanism(s) of granulocytes may be involved in the killing of cancer cells in SR/CR mice.
authors.affiliation: Department of Pathology, Wake Forest University School of Medicine Winston-Salem, North Carolina, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Sanders
authors.forename: John R
authors.initials: JR
authors.lastname: Stehle
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Blanks
authors.forename: Gregory
authors.initials: G
authors.lastname: Riedlinger
authors.forename: Jung W
authors.initials: JW
authors.lastname: Kim-Shapiro
authors.forename: Arta M
authors.initials: AM
authors.lastname: Monjazeb
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Adams
authors.forename: Mark C
authors.initials: MC
authors.lastname: Willingham
authors.forename: Zheng
authors.initials: Z
authors.lastname: Cui
mesh_terms: D000818:Animals; D005260:Female; D020022:Genetic Predisposition to Disease; D007962:Leukocytes / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics*; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000276:immunology*; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics*
chemical_list: D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; C483886:perforin, mouse; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases