Perforin-mediated cytotoxicity is critical for surveillance of spontaneouslymphoma

Immune surveillance by cytotoxic lymphocytes against cancer has been postul ated for decades, but direct evidence for the role of cytotoxic lymphocytes in protecting against spontaneous malignancy has been lacking. As the reje ction of many experimental cancers by cytotoxic T lymphocytes and natural k iller cells is dependent on the pore-forming protein perforin (pfp), we exa mined pfp-deficient mice for increased cancer susceptibility. Here we show that pfp-deficient mice have a high incidence of malignancy in distinct lym phoid cell lineages (T, B, NKT), indicating a specific requirement for pfp in protection against lymphomagenesis. The susceptibility to lymphoma was a ccentuated 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 p5 3-deficient mice. Pfp-deficient mice were at least 1,000-fold more suscepti ble to these lymphomas when transplanted, compared with immunocompetent mic e in which tumor rejection was controlled by CD8(+) T lymphocytes. This stu dy is the first that implicates direct cytotoxicity by lymphocytes in regul ating lymphomagenesis.