Article thumbnail
Location of Repository

Interferon γ–independent Rejection of Interleukin 12–transduced Carcinoma Cells Requires CD4+ T Cells and Granulocyte/Macrophage Colony–stimulating Factor

By Chiara Zilocchi, Antonella Stoppacciaro, Claudia Chiodoni, Mariella Parenza, Nadia Terrazzini and Mario P. Colombo

Abstract

We analyzed the ability of interferon (IFN)-γ knockout mice (GKO) to reject a colon carcinoma transduced with interleukin (IL)-12 genes (C26/IL-12). Although the absence of IFN-γ impaired the early response and reduced the time to tumor onset in GKO mice, the overall tumor take rate was similar to that of BALB/c mice. In GKO mice, C26/IL-12 tumors had a reduced number of infiltrating leukocytes, especially CD8 and natural killer cells. Analysis of the tumor site, draining nodes, and spleens of GKO mice revealed reduced expression of IFN- inducible protein 10 and monokine induced by γ-IFN. Despite these defects, GKO mice that rejected C26/IL-12 tumor, and mice that were primed in vivo with irradiated C26/IL-12 cells, showed the same cytotoxic T lymphocyte activity but higher production of granulocyte/macrophage colony–stimulating factor (GM-CSF) as compared with control BALB/c mice. Treatment with monoclonal antibodies against GM-CSF abrogated tumor regression in GKO but not in BALB/c mice. CD4 T lymphocytes, which proved unnecessary or suppressive during rejection of C26/IL-12 cells in BALB/c mice, were required for tumor rejection in GKO mice. CD4 T cell depletion was coupled with a decline in GM-CSF expression by lymphocytes infiltrating the tumors or in the draining nodes, and with the reduction and disappearance of granulocytes and CD8 T cells, respectively, in tumor nodules. These results suggest that GM-CSF can substitute for IFN-γ in maintaining the CD8–polymorphonuclear leukocyte cross-talk that is a hallmark of tumor rejection

Topics: Articles
Publisher: The Rockefeller University Press
OAI identifier: oai:pubmedcentral.nih.gov:2525540
Provided by: PubMed Central

Suggested articles

Citations

  1. (1993). Antitumor and antimetastatic activity of interleukin 12 against murine tumors.
  2. (1997). Antitumor efficacy of adenocarcinoma cells engineered to produce interleukin 12 (IL-12) or other cytokines compared with exogenous IL-12.
  3. (1995). CD4 T cells inhibits in vivo the CD8-mediated immune response against murine colon carcinoma cells transduced with IL-12 genes.
  4. (1996). Cytokine and chemokine expression in tumors of mice receiving systemic therapy with IL-12.
  5. (1994). Cytokine gene transfer in tumor inhibition and tentative tumor therapy: where are we now?
  6. (1991). Cytokines in the context.
  7. (1997). Cytokines, tumorcell death and immunogenicity: a question of choice.
  8. (1994). Cytotoxic T lymphocytes recognize tumor antigens of a murine colonic carcinoma by using different T-cell receptors.
  9. (1996). Genetic absence of gamma-interferon delays but does not prevent diabetes in NOD mice.
  10. (1995). Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo.
  11. (1996). IL-12 potentiates the curative effect of a vaccine based on IL-2 transduced tumor cells. Cancer Res.
  12. IL-12 receptors and receptor antagonists.
  13. (1987). Immune interferon enhances functional properties of human granulocytes: role of Fc receptors and effect of lymphotoxin, tumor necrosis factor, and granulocytemacrophage colony-stimulating factor.
  14. (1996). Immunotherapy of experimental metastases by vaccination with interleukin gene-transduced adenocarcinoma cells sharing tumor-associated antigens. Comparison between IL-12 and IL-2 genetransduced tumor cell vaccines.
  15. (1994). In vitro predictors of therapeutic response in melanoma patients receiving tumor-infiltrating lymphocytes and interleukin-2.
  16. (1996). Inhibition of angiogenesis by interleukin-12 is mediated by interferoninducible protein 10.
  17. (1995). Inhibition of angiogenesis in vivo by interleukin 12.
  18. (1989). Interaction of mammalian cells with polymorphonuclear leukocytes: relative sensitivity to monolayer disruption and killing.
  19. (1991). Interferon g and tumor necrosis factor have a role in tumor regressions mediated by murine CD81 tumor-infiltrating lymphocytes.
  20. (1994). Interferon g-independent effects of interleukin 12 administered during acute or established infection due to Leishmania major.
  21. (1993). Interleukin 12 in host defense against microbial pathogens.
  22. (1995). Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridges innate resistance and antigen-specific adaptive immunity.
  23. (1997). Intracellular antimicrobial activity in the absence of interferon-g: effect of interleukin-12 in experimental visceral leishmaniasis in interferon-g gene-disrupted mice.
  24. (1993). IP-10, a -C-X-C- chemokine, elicits a potent thymus-dependent antitumor response in vivo.
  25. Local cytokine availability elicits tumor rejection and systemic immunity through granulocyte–T-lymphocyte crosstalk. Cancer Res.
  26. (1993). Multiple defects of immune cell function in mice with disrupted interferon-g genes.
  27. (1993). Neutrophil-mediated damage to human vascular endothelium. Role of cytokine activation.
  28. (1996). primes macrophages for nitric oxide production in vivo and restores depressed nitric oxide production by macrophages from tumor-bearing mice: implications for the antitumor activity of interleukin 12 and/or interleukin 2. Cancer Res.
  29. (1994). Recombinant IL-12 administration induces tumor regression in association with IFNg production.
  30. (1993). Regression of an established tumor genetically modified to release granulocyte colony–stimulating factor requires granulocyte–T cell cooperation and T cell–produced interferon g.
  31. (1997). Regulation of the interleukin (IL)-12Rb2 subunit expression in developing T helper 1 (Th1) and Th2 cells.
  32. (1988). Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages: comparison of activating cytokines and evidence for independent production.
  33. (1994). Requirement of vascular integrin avb3 for angiogenesis.
  34. (1995). Role of IFNg in mediating the antitumor efficacy of interleukin-12.
  35. (1992). Role of neutrophils and CD41 T lymphocytes in the primary and memory response to nonimmunogenic murine mammary adenocarcinoma made immunogenic by IL-2 gene transfection.
  36. Role of neutrophils and lymphocytes in inhibition of a mouse mammary adenocarcinoma engineered to release IL-2, IL-4, IL-7, IL-10, IFN-alpha, IFN-gamma, and TNF-alpha.
  37. (1995). Specific immunity to Listeria monocytogenes in the absence of IFNg.
  38. (1995). Systemic administration of rIL-12 induces complete tumor regression and protective immunity: response is correlated with a striking reversal of suppressed IFNg production by anti-tumor T cells.
  39. (1996). The amount of IL-12 available at the tumor site is critical for tumor regression. Cancer Res.
  40. (1996). The immunodominant major histocompatibility complex class I–restricted antigen of a murine colon tumor derives from an endogenous retroviral gene product.
  41. (1995). The IP-10 chemokine binds to a specific cell surface heparan sulfate site shared with platelet factor 4 and inhibits endothelial cell proliferation.
  42. The role of IL-12 in the induction of organ-specific autoimmune diseases.
  43. (1975). Tumor induction relationships in development of transplantable cancers of the colon in mice for chemotherapy assay, with a note on carcinogen structure. Cancer Res.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.