Suppression of lymphoma and epithelial malignancies effected by interferon gamma

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.

Figure 1.

Pfp and IFN-γ protect mice from spontaneous lymphoma. The appearance of tumors was recorded in mice of (A) C57BL/6 and (B) BALB/c backgrounds as indicated. Groups of mice (number in parentheses) were evaluated on a weekly basis and, when moribund, tumor type (white squares, thymic lymphoma; black squares, disseminated lymphoma; black triangles, sarcoma; white triangles, lung adenocarcinoma; and white circles, other tumors) recorded against the age at the time of death/autopsy (in days). *, disseminated lymphomas of histiocyte morphology. No tumors were observed in heterozygote control groups of (B6 × B6 IFN-γ^−/−)F1(n = 17), (BALB/c × BALB/c IFN-γ^−/−)F1 (n = 12), and (BALB/c × BALB/c pfp^−/−)F1 (n = 18) mice over a 750-d period. A small number of the oldest surviving BALB/c IFN-γ^−/− mice (700–750 d) also developed nonmalignant mucosal hamartomas in the stomach.

Figure 1.

Pfp and IFN-γ protect mice from spontaneous lymphoma. The appearance of tumors was recorded in mice of (A) C57BL/6 and (B) BALB/c backgrounds as indicated. Groups of mice (number in parentheses) were evaluated on a weekly basis and, when moribund, tumor type (white squares, thymic lymphoma; black squares, disseminated lymphoma; black triangles, sarcoma; white triangles, lung adenocarcinoma; and white circles, other tumors) recorded against the age at the time of death/autopsy (in days). *, disseminated lymphomas of histiocyte morphology. No tumors were observed in heterozygote control groups of (B6 × B6 IFN-γ^−/−)F1(n = 17), (BALB/c × BALB/c IFN-γ^−/−)F1 (n = 12), and (BALB/c × BALB/c pfp^−/−)F1 (n = 18) mice over a 750-d period. A small number of the oldest surviving BALB/c IFN-γ^−/− mice (700–750 d) also developed nonmalignant mucosal hamartomas in the stomach.

Figure 2.

Distinct behavior of lymphomas arising in B6 pfp^−/− mice and B6 IFN-γ^2/− mice. Primary lymphomas arising in B6 pfp^−/− (top) and B6.IFN-γ^2/− (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).