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Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma
M J Smyth1, K Y Thia, S E Street
1Austin Research Institute, Heidelberg, 3084, Victoria, Australia.
Abstract:
Immune surveillance by cytotoxic lymphocytes against cancer has been postulated for decades, but direct evidence for the role of cytotoxic lymphocytes in protecting against spontaneous malignancy has been lacking. As the rejection of many experimental cancers by cytotoxic T lymphocytes and natural killer cells is dependent on the pore-forming protein perforin (pfp), we examined pfp-deficient mice for increased cancer susceptibility. Here we show that pfp-deficient mice have a high incidence of malignancy in distinct lymphoid cell lineages (T, B, NKT), indicating a specific requirement for pfp in protection against lymphomagenesis. The susceptibility to lymphoma was accentuated by simultaneous lack of expression of the p53 gene, mutations in which also commonly predispose to human malignancies, including lymphoma. In contrast, the incidence and age of onset of sarcoma was unaffected in p53-deficient mice. Pfp-deficient mice were at least 1,000-fold more susceptible to these lymphomas when transplanted, compared with immunocompetent mice in which tumor rejection was controlled by CD8(+) T lymphocytes. This study is the first that implicates direct cytotoxicity by lymphocytes in regulating lymphomagenesis.
Insights
Cytotoxic lymphocytes use perforin (pfp) to prevent cancer. Pfp-deficient mice developed lymphomas, demonstrating pfp
Area of Science:
- Immunology
- Cancer Biology
- Genetics
Background:
- Immune surveillance by cytotoxic lymphocytes is crucial for preventing cancer.
- The role of cytotoxic lymphocytes in protection against spontaneous malignancy has lacked direct evidence.
- Perforin (pfp) is essential for cytotoxic T lymphocyte and natural killer cell-mediated rejection of experimental cancers.
Purpose of the Study:
- To investigate the role of perforin (pfp) in protection against spontaneous lymphomagenesis.
- To determine if pfp deficiency increases cancer susceptibility, particularly lymphoma.
- To examine the interplay between pfp deficiency and p53 gene mutations in cancer development.
Main Methods:
- Analysis of cancer incidence in perforin (pfp)-deficient mice.
- Evaluation of lymphoma susceptibility in pfp-deficient mice with and without p53 gene expression.
- Transplantation studies comparing lymphoma susceptibility in pfp-deficient and immunocompetent mice.
Main Results:
- Pfp-deficient mice exhibited a high incidence of malignancy in lymphoid cell lineages (T, B, NKT).
- Lymphoma susceptibility was exacerbated by the concurrent absence of the p53 gene.
- Pfp-deficient mice were over 1,000-fold more susceptible to transplanted lymphomas compared to immunocompetent mice.
Conclusions:
- This study provides the first direct evidence implicating lymphocyte-mediated cytotoxicity in regulating lymphomagenesis.
- Perforin (pfp) plays a critical role in preventing spontaneous lymphoma development.
- The p53 tumor suppressor gene cooperates with pfp in preventing lymphomagenesis.