ABSTRACT
66Human blood natural killer (NK) cells and monocytes display minimal spontaneous cytotoxicity against fresh melanoma and other solid tumor cells. Recombinant interleukin-2 (rIL-2) and interferon-γ (rIFN-γ) activate NK cells and monocytes, respectively, resulting in significant cytolysis of fresh solid tumor cells. Most of the lymphokine-activated killer (LAK) activity is mediated by rIL-2-activated CD3-,CD16 + NK cells. Blood T cells have no spontaneous cytotoxicity against solid tumor cells, nor are they activated by rIL-2 alone or the other lymphokines. However, unstimulated Leu 7+ blood T cells lyse fresh solid tumor cells in the presence of Con A. This lectin-dependent lysis is inhibited by adding anti-CD3 monoclonal antibody to the effector phase, suggesting that some Leu 7+ T cells are cytotoxic T lymphocytes (CTL) generated in vivo against autologous tumor cells, virus-infected cells, or other target cells. These Leu 7+ T cells partly account for LAK activity generated in vitro in cultures of PBMC with IL-2.
Cancer patients with metastatic melanoma display a serum-borne factor that suppresses LAK cell induction. The presence of this serum suppressor factor (SSF) strongly correlates with disease stage. Further, recombinant interleukin-4 (rIL-4) is a potent inhibitor against LAK cell induction. Both SSF and rIL-4 work at least additively in the inhibition of LAK cell induction. Addition of rIFN-γ to the rIL-2 culture overcomes SSF- as well as rIL-4-mediated suppression.
In contrast to T cells from peripheral blood, T cells in the infiltrate of solid tumor (tumor-infiltrating lymphocytes [TIL]) are capable of being activated in culture with rIL-2 alone. TIL from metastatic melanomas increase in number by more than 1000-fold in culture with rIL-2 alone. These rIL-2-activated TIL have consistent and potent CTL activity restricted to fresh autologous melanoma cells. There are few or no NK cells before or after expansion with rIL-2, respectively, in melanoma tumor sites. T cell receptor αβ on effector TIL is involved in the specific immune-recognition of the targets by the CTL. TIL from renal cell carcinoma also increased in number by more than 1000-fold in culture with rIL-2 alone. rIL-2-activated TIL from renal cell carcinoma contain both CD3+ T cells and CD16+ NK cells. Both of these effectors display MHC-nonrestricted cytotoxicity (LAK activity) against fresh solid tumor cells, although the levels of cytotoxicity by CD16+ NK cells are much higher than those of T cells.
In summary, IL-2 activates NK cells from peripheral blood. It activates T cells from melanoma tumor sites, or both NK cells and T cells from renal cell carcinoma. IFN-γ activates monocytes. These lymphokine-activated cells display significant levels of cytotoxicity against solid tumor cells. SSF and IL-4 inhibit rIL-2-induced LAK cell activity. IFN-γ overcomes these suppressive effects. These results suggest that NK cells and monocytes are important in preventing the hematogenous dissemination of tumor cells. T cells in the infiltrate of tumor may act to destroy melanoma tumor cells. Both NK and T cells in the infiltrate of renal cell carcinoma may be important in the tumor regression.
