A model for CD8(+) CTL tumor immunosurveillance and regulation of tumor escape by CD4 T cells through an effect on quality of CTL

Understanding immune mechanisms influencing cancer regression, recurrence, and metastasis may be critical to developing effective immunotherapy, Using a tumor expressing HIV gp160 as a model viral tumor Ag, we found a growth- regression-recurrence pattern, and used this to investigate mechanisms of i mmunosurveillance. Regression was dependent on CD8 T cells, and recurrent t umors were resistant to CTL, had substantially reduced expression of epitop e mRNA, but retained the gp160 gene, MHC, and processing apparatus, Increas ing CTL numbers by advance priming with vaccinia virus expressing gp160 pre vented only the initial tumor growth but not the later appearance of escape variants. Unexpectedly, CD4 cell depletion protected mice from tumor recur rence, whereas IL-4 knockout mice, deficient in Th2 cells, did not show thi s protection, and IFN-gamma knockout mice were more susceptible, Purified C D8 T cells from CD4-depleted mice following tumor regression had more IFN-g amma mRNA and lysed tumor cells without stimulation ex vivo, in contrast to CD4-intact mice. Thus, the quality as well as quantity of CD8(+) CTL deter mines the completeness of immunosurveillance and is controlled by CD4 T cel ls but not solely Th2 cytokines, This model of immunosurveillance may indic ate ways to enhance the efficacy of surveillance and improve immunotherapy.