Perforin-Mediated Cytotoxicity Is Critical for Surveillance of Spontaneous Lymphoma

By M. Smyth, K. Thia, Shayna E. A. Street, D. MacGregor, D. Godfrey, J. Trapani. Journal of Experimental Medicine, 2000

609 citations recorded by the source corpus.

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.

Subfields: Hematology, Immunology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/b2e954697184009b70c176f332d3be7525831624

How researchers see this paper

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In Hematology

1. M. Smyth
2. Robert Schreiber
3. J. Trapani
4. G. Dunn
5. Y. Hayakawa
6. J. Massagué
7. Dori A. Thomas

In Immunology

1. M. Smyth
2. Robert Schreiber
3. G. Dunn
4. Lloyd J. Old
5. G. Dranoff
6. J. Trapani
7. N. Xiong
8. H. Yagita

Citations in the corpus

• How Do Cytotoxic Lymphocytes Kill Cancer Cells? (2015, background): “This seems to be specially relevant for tumors of hematologic origin as PRF1 knockout mice develop spontaneous B lymphoma (34).”
• New aspects of natural-killer-cell surveillance and therapy of cancer (2002, background): “cgi?l=5551">perforin or IFN-γ, has provided evidence of CTL-mediated protection from spontaneous tumour”
• Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. (2007, background): “Perforin-deficient (Prf1 / ) mice are more susceptible to the development of spontaneous lymphomas (Smyth et al., 2000b), suggesting that the perforin-granzyme pathway is an important component of tumor surveillance.”
• Modulation of the anti-tumor immune response by complement (2008, result): “Several studies with animal experimental models, as well as studies in humans, have demonstrated a crucial function for cytotoxic CD8 + T cells in adaptive immunity to tumor”
• Natural selection of tumor variants in the generation of “tumor escape” phenotypes (2002, result): “Other studies have shown that in perforin-deficient mice, there is a higher rate of spontaneous lymphoma and lung adenocarcinom”
• Functional significance of the perforin/granzyme cell death pathway (2002, background): “A widespread role for perforin in immunosurveillance and immunoregulation has been strengthened by the observed high incidence of spontaneous malignancy, particularly B-cell lymphoma, in perforin-deficient mic”
• The Molecular Mechanism of Natural Killer Cells Function and Its Importance in Cancer Immunotherapy (2017, background): “The perforin-dependent NK cell activity was reported to control B cell lymphomas and mammary carcinoma (132).”