BREAKING IMMUNOLOGICAL TOLERANCE TO TUMOR CELLS AS A NOVEL IMMUNOTHERAPY FOR CANCER

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We show that removal of a T cell subpopulation can evoke effective tumor immunity in otherwise non-responding animals. Elimination of CD25-expressing T cells, which constitute 5-10% of peripheral CD4^+ T cells in normal naive mice, elicited potent immune responses to syngeneic tumors in vivo and eradicated them. The responses were mediated by tumor-specific CD8^+ CTLs and tumor-nonspecific CD4^-8^- cytotoxic cells akin to NK cells. Furthermore, in vitro culture of CD25^+4^+ T cell-depleted splenic cell suspensions prepared from tumor-unsensitized normal mice led to spontaneous generation of similar CD4^-8^- cytotoxic cells capable of killing a broad spectrum of tumors ; reconstitution of CD25^+4^+ T cells inhibited the generation. In this culture, self-reactive CD25^-4^+ T cells responding to self peptides/class II MHC complexes on APCs spontaneously proliferated upon removal of CD^+4^+ T cells, secreting large amounts of IL-2. The IL-2 thus produced appeared to be responsible for the generation of CD4^-8^- NK cells as lymphokine-activated killer cells, because direct addition of an equivalent amount of IL-2 to the culture of CD4^-8^- cells generated similar lymphokine-activated killer/NK cells, whereas coculture of normal CD4^-8^- cells with CD25^-4^+ T cells from IL-2-deficient mice did not. Thus, removal of immunoregulatory CD25^+4^+ T cells can abrogate immunological unresponsiveness to syngenic tumors in vivo and in vitro, leading to spontaneous development of tumor-specific effector cells as well as tumor-nonspecific ones. This novel way of evoking tumor immunity would help to devise effective immunotherapy for cancer in humans.