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Suppression of lymphoma and epithelial malignancies effected by interferon gamma.

Street SE, Trapani JA, MacGregor D, Smyth MJ - J. Exp. Med. (2002)

Bottom Line: Herein, we describe spontaneous tumor development in gene-targeted mice lacking interferon (IFN)-gamma and/or perforin (pfp), or the immunoregulatory cytokines, interleukin (IL)-12, IL-18, and tumor necrosis factor (TNF).Both IFN-gamma and pfp were critical for suppression of lymphomagenesis, however the level of protection afforded by IFN-gamma was strain specific.A significant incidence of late onset adenocarcinoma observed in both IFN-gamma- and pfp-deficient mice indicated that some epithelial tissues were also subject to immunosurveillance.

View Article: PubMed Central - PubMed

Affiliation: Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Institute, East Melbourne, Victoria 8006, Australia.

ABSTRACT
The immunosurveillance of transformed cells by the immune system remains one of the most controversial and poorly understood areas of immunity. Gene-targeted mice have greatly aided our understanding of the key effector molecules in tumor immunity. Herein, we describe spontaneous tumor development in gene-targeted mice lacking interferon (IFN)-gamma and/or perforin (pfp), or the immunoregulatory cytokines, interleukin (IL)-12, IL-18, and tumor necrosis factor (TNF). Both IFN-gamma and pfp were critical for suppression of lymphomagenesis, however the level of protection afforded by IFN-gamma was strain specific. Lymphomas arising in IFN-gamma-deficient mice were very nonimmunogenic compared with those derived from pfp-deficient mice, suggesting a comparatively weaker immunoselection pressure by IFN-gamma. Single loss of IL-12, IL-18, or TNF was not sufficient for spontaneous tumor development. A significant incidence of late onset adenocarcinoma observed in both IFN-gamma- and pfp-deficient mice indicated that some epithelial tissues were also subject to immunosurveillance.

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Distinct behavior of lymphomas arising in B6 pfp−/− mice and B6 IFN-γ2/− mice. Primary lymphomas arising in B6 pfp−/− (top) and B6.IFN-γ2/− (bottom) were secondarily transplanted intraperitoneally (101–107 cells in 0.2 ml PBS, as indicated) into groups of five untreated B6 WT (black circles or squares), B6 pfp−/− (white circles) or B6 IFN-γ−/− (white squares) mice. Mice were monitored for 100 d and each symbol depicts an individual mouse. Tumor-free mice are indicated above the horizontal line. The results are representative of seven primary lymphomas and three primary lymphomas transplanted from B6 pfp−/− and B6 IFN-γ−/− mice, respectively. Top, PNK-7 (B cell lymphoma from B6 pfp−/− mouse); bottom, BG18 (T cell lymphoma from B6 IFN-γ−/− mouse).
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fig2: Distinct behavior of lymphomas arising in B6 pfp−/− mice and B6 IFN-γ2/− mice. Primary lymphomas arising in B6 pfp−/− (top) and B6.IFN-γ2/− (bottom) were secondarily transplanted intraperitoneally (101–107 cells in 0.2 ml PBS, as indicated) into groups of five untreated B6 WT (black circles or squares), B6 pfp−/− (white circles) or B6 IFN-γ−/− (white squares) mice. Mice were monitored for 100 d and each symbol depicts an individual mouse. Tumor-free mice are indicated above the horizontal line. The results are representative of seven primary lymphomas and three primary lymphomas transplanted from B6 pfp−/− and B6 IFN-γ−/− mice, respectively. Top, PNK-7 (B cell lymphoma from B6 pfp−/− mouse); bottom, BG18 (T cell lymphoma from B6 IFN-γ−/− mouse).

Mentions: The malignancy of primary tumors arising was additionally confirmed by secondary transfer into mice of the same strain. Two representative experiments of >10 using different disseminated lymphomas transferred from either B6 pfp−/− or B6 IFN-γ−/− mice are depicted in Fig. 2. The transfer of three different T cell lymphomas from B6 IFN-γ−/− mice (one shown) demonstrated that these tumors grew at a similar rate in B6 IFN-γ−/− and B6 WT mice (Fig. 2). By contrast, and in concert with our previous data (16), all B cell lymphomas from B6 pfp−/− mice grew at low cell numbers in B6 pfp−/− mice, but were avidly rejected when transferred into B6 WT mice (Fig. 2). Thus far, all lymphomas of B cell origin arising in pfp−/− mice, including five described herein, were rejected in WT mice by CD8+ T cells (reference 16 and unpublished data) and in this study the donor tumor cells and recipient mice were genetically matched as closely as possible. Similar experiments with three different B cell lymphomas from BALB/c pfp−/− mice have also demonstrated rejection in BALB/c WT mice and (BALB/c × BALB/c. pfp−/−)F1 heterozygous mice, but not BALB/c pfp−/− mice (unpublished data). In concert with our previous lymphoma transfer studies (16), it is likely that the lymphomas of B cell origin are generally being detected by CD8+ T cells independently of any alloantigens potentially expressed by the tumor. It is probable that the lack of detectable immunogenicity of lymphomas from IFN-γ−/− mice indicates an important functional distinction between the activities of IFN-γ and pfp in eliminating potentially transformed cells. Consistent with the immune system functioning as a tumor-suppressor system, our results indicated that the immunoselection pressure of pfp on tumor cells was strong. Lymphomas from pfp-deficient mice have emerged in the absence of this significant immunoselection pressure, and they are avidly rejected in WT mice upon transfer. Immunoselection by IFN-γ appears far weaker from our spontaneous lymphoma transplant data, however it has been demonstrated in an experimental system using MCA fibrosarcomas arising in IFN-γ receptor-deficient mice (36).


Suppression of lymphoma and epithelial malignancies effected by interferon gamma.

Street SE, Trapani JA, MacGregor D, Smyth MJ - J. Exp. Med. (2002)

Distinct behavior of lymphomas arising in B6 pfp−/− mice and B6 IFN-γ2/− mice. Primary lymphomas arising in B6 pfp−/− (top) and B6.IFN-γ2/− (bottom) were secondarily transplanted intraperitoneally (101–107 cells in 0.2 ml PBS, as indicated) into groups of five untreated B6 WT (black circles or squares), B6 pfp−/− (white circles) or B6 IFN-γ−/− (white squares) mice. Mice were monitored for 100 d and each symbol depicts an individual mouse. Tumor-free mice are indicated above the horizontal line. The results are representative of seven primary lymphomas and three primary lymphomas transplanted from B6 pfp−/− and B6 IFN-γ−/− mice, respectively. Top, PNK-7 (B cell lymphoma from B6 pfp−/− mouse); bottom, BG18 (T cell lymphoma from B6 IFN-γ−/− mouse).
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fig2: Distinct behavior of lymphomas arising in B6 pfp−/− mice and B6 IFN-γ2/− mice. Primary lymphomas arising in B6 pfp−/− (top) and B6.IFN-γ2/− (bottom) were secondarily transplanted intraperitoneally (101–107 cells in 0.2 ml PBS, as indicated) into groups of five untreated B6 WT (black circles or squares), B6 pfp−/− (white circles) or B6 IFN-γ−/− (white squares) mice. Mice were monitored for 100 d and each symbol depicts an individual mouse. Tumor-free mice are indicated above the horizontal line. The results are representative of seven primary lymphomas and three primary lymphomas transplanted from B6 pfp−/− and B6 IFN-γ−/− mice, respectively. Top, PNK-7 (B cell lymphoma from B6 pfp−/− mouse); bottom, BG18 (T cell lymphoma from B6 IFN-γ−/− mouse).
Mentions: The malignancy of primary tumors arising was additionally confirmed by secondary transfer into mice of the same strain. Two representative experiments of >10 using different disseminated lymphomas transferred from either B6 pfp−/− or B6 IFN-γ−/− mice are depicted in Fig. 2. The transfer of three different T cell lymphomas from B6 IFN-γ−/− mice (one shown) demonstrated that these tumors grew at a similar rate in B6 IFN-γ−/− and B6 WT mice (Fig. 2). By contrast, and in concert with our previous data (16), all B cell lymphomas from B6 pfp−/− mice grew at low cell numbers in B6 pfp−/− mice, but were avidly rejected when transferred into B6 WT mice (Fig. 2). Thus far, all lymphomas of B cell origin arising in pfp−/− mice, including five described herein, were rejected in WT mice by CD8+ T cells (reference 16 and unpublished data) and in this study the donor tumor cells and recipient mice were genetically matched as closely as possible. Similar experiments with three different B cell lymphomas from BALB/c pfp−/− mice have also demonstrated rejection in BALB/c WT mice and (BALB/c × BALB/c. pfp−/−)F1 heterozygous mice, but not BALB/c pfp−/− mice (unpublished data). In concert with our previous lymphoma transfer studies (16), it is likely that the lymphomas of B cell origin are generally being detected by CD8+ T cells independently of any alloantigens potentially expressed by the tumor. It is probable that the lack of detectable immunogenicity of lymphomas from IFN-γ−/− mice indicates an important functional distinction between the activities of IFN-γ and pfp in eliminating potentially transformed cells. Consistent with the immune system functioning as a tumor-suppressor system, our results indicated that the immunoselection pressure of pfp on tumor cells was strong. Lymphomas from pfp-deficient mice have emerged in the absence of this significant immunoselection pressure, and they are avidly rejected in WT mice upon transfer. Immunoselection by IFN-γ appears far weaker from our spontaneous lymphoma transplant data, however it has been demonstrated in an experimental system using MCA fibrosarcomas arising in IFN-γ receptor-deficient mice (36).

Bottom Line: Herein, we describe spontaneous tumor development in gene-targeted mice lacking interferon (IFN)-gamma and/or perforin (pfp), or the immunoregulatory cytokines, interleukin (IL)-12, IL-18, and tumor necrosis factor (TNF).Both IFN-gamma and pfp were critical for suppression of lymphomagenesis, however the level of protection afforded by IFN-gamma was strain specific.A significant incidence of late onset adenocarcinoma observed in both IFN-gamma- and pfp-deficient mice indicated that some epithelial tissues were also subject to immunosurveillance.

View Article: PubMed Central - PubMed

Affiliation: Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Institute, East Melbourne, Victoria 8006, Australia.

ABSTRACT
The immunosurveillance of transformed cells by the immune system remains one of the most controversial and poorly understood areas of immunity. Gene-targeted mice have greatly aided our understanding of the key effector molecules in tumor immunity. Herein, we describe spontaneous tumor development in gene-targeted mice lacking interferon (IFN)-gamma and/or perforin (pfp), or the immunoregulatory cytokines, interleukin (IL)-12, IL-18, and tumor necrosis factor (TNF). Both IFN-gamma and pfp were critical for suppression of lymphomagenesis, however the level of protection afforded by IFN-gamma was strain specific. Lymphomas arising in IFN-gamma-deficient mice were very nonimmunogenic compared with those derived from pfp-deficient mice, suggesting a comparatively weaker immunoselection pressure by IFN-gamma. Single loss of IL-12, IL-18, or TNF was not sufficient for spontaneous tumor development. A significant incidence of late onset adenocarcinoma observed in both IFN-gamma- and pfp-deficient mice indicated that some epithelial tissues were also subject to immunosurveillance.

Show MeSH
Related in: MedlinePlus