The in vivo expansion rate of properly stimulated transferred CD8+ T cells exceeds that of an aggressively growing mouse tumor

摘要

It has been hypothesized that rapidly dividing tumor cells can outpace adoptively transferred anti-tumor lymphocytes when tumors are large. However, this hypothesis is at odds with clinical observations indicating that bulky tumors can be destroyed by small numbers of adoptively transferred anti-tumor T cells. We sought to measure the relative growth rates of T cells and tumor cells in a model using transgenic CD8⁺ T cells specific for the gp10025–33 H-2D^b epitope (called pmel-1) to treat large, well-established subcutaneous B16 melanoma. We tested the impact of the immunization using an altered-peptide ligand vaccine alone or in combination with IL-2 by analyzing the kinetics of T cell expansion using direct enumeration. We found that pmel-1 T cells proliferated explosively during a 5-day period following transfer. Calculations from net changes in population suggest that at the peak of cell division, pmel-1 T cells divide at a rate of 5.3 hours/cell division, which was much faster than B16 tumor cells during optimal growth (24.9 hours/cell division). These results clearly indicate that the notion of a kinetic “race” between the tumor and lymphocyte is no contest when adoptively transferred cells are stimulated with immunization and IL-2. When appropriately stimulated, tumor-reactive T cell expansion can far exceed the growth of even an aggressively growing mouse tumor.