CD40 ligation restores cytolytic T lymphocyte response and eliminates fibrosarcoma in the peritoneum of mice lacking CD4+ T cells
We investigated whether the responsiveness of anti-tumor CD4+ T cells suppressed in the tumor-bearing state is reversed in conditions free of tumor burden. Spleen cells from BALB/c mice bearing a syngeneic tumor (CSA1M) 1-3 wk after inoculation with CSA1M cells produced interleukin-2 (IL-2) and IL-4 upon in vitro culture without addition of exogenous tumor antigens. This lymphokine production was achieved through collaboration between anti-CSA1M CD4+ T cells and antigen-presenting cells (APC) that had been pulsed with CSA1M tumor antigens in vivo in the tumor-bearing state. However, spleen cells from late (8-10 wk) tumor-bearing stages produced reduced levels of lymphokine production despite the presence of comparable proportions of CD4+ T cells. Because APC in these cell populations exhibited enhanced capacities to present tumor antigens, reduced responsiveness was ascribed to the dysfunction of CD4+ T cells themselves. When spleen cells from early tumor-bearing mice were preincubated for 1-2 days and recultured in fresh medium, the magnitude of lymphokine production by these cells was not changed. In contrast, the same protocol of preincubation and reculture for cells from late tumor-bearing mice resulted in the recovery of anti-tumor lymphokine-producing capacity. The recovered capacity was comparable to or slightly higher than that expressed by cells from early tumor-bearing stages. Since the CD4+ T cell content did not significantly differ before and after preincubation, enhanced lymphokine production was due to the recovered responsiveness of anti-tumor CD4+ helper T cells. The recovery of anti-tumor responsiveness was also induced in vivo by tumor removal at the late tumor-bearing stage: spleen cells from mice 2-4 wk after tumor resection efficiently produced IL-2 and IL-4. These results indicate that the immunodysfunction of anti-tumor CD4+ T cells induced in the tumor-bearing state is reversible because release from tumor burden either by preincubation in vitro or by tumor removal in vivo results in almost complete recovery of the potent anti-tumor responsiveness initially expressed.