Researchers may be closer to understanding why anti-cancer drugs such as Ipilimumab, which boost the tumor-killing power of immune cells, haven't fared well in clinical trials, according to a new study published online Monday in the Journal of Experimental Medicine.
The immune system's tumor-fighting T cells work best when maximally activated. Scientists have achieved this by blocking molecules that dampen the cells' activation, or by removing a population of regulatory T cells that block the killing ability of tumor-specific T cells. But neither approach has worked well in patients with established tumors, according to Sergio A. Quezada, of the Howard Hughes Medical Institute and the Ludwig Center for Cancer Immunotherapy, at Memorial Sloan-Kettering Cancer Center in New York City, co-author of the study.
Using B16/BL6, a transplantable murine melanoma model, Quezada and colleagues showed a dichotomy between the effects of T reg cell depletion on tumor rejection dependent on whether depletion occurs before (prophylactic) or after (therapeutic) tumor engraftment.
The results showed that failure to promote rejection with therapeutic depletion was not related to lack of T reg cell depletion, to elimination of CD25+ effector T cells, or to a failure to enhance systemic antitumor T cell responses. Instead, the researchers said that it correlates with failure of effector cells to infiltrate the tumor and increase the intratumor ratio of effector T cell/T reg cell.
Finally, systemic antitumor responses generated upon therapeutic T reg cell depletion are significantly stronger than those generated in the presence of T reg cells, and are capable of eliciting rejection of established tumors after transfer into immunoablated recipients receiving combination immunotherapy, the authors wrote.
The researchers concluded that the results demonstrated a dissociation between measurable systemic responses and tumor rejection during CD25-directed T reg cell depletion, and suggested that some quality of large tumors makes them resistant to T cell killing.