Preferential Proliferation of T Effectors and Tumor Protection by Adoptive Transfer of Primed Anti-Lymphoma Splenocytes into Lymphodepleted Hosts.

Clinical trials of immunotherapy for lymphoma have demonstrated induction of immunologic anti-tumor responses but only a minority of clinical responses. Possible reasons include tumor-produced factors (e.g. IL10, VEGF, TGFβ) and immune-regulatory mechanisms (e.g. Tregs, immature myeloid cells, tumor-associated macrophages). Immunotherapy in the post-transplant setting could overcome both these obstacles, as it is a state of minimal residual disease and of relative lympho- and myelodepletion. We have previously described a method of CD8 T cell-dependent vaccination against established lymphoma tumors by a combination of chemotherapy and intra-tumoral injection of the TLR9 agonist CpG oligodeoxynucleotides. Herein, we transferred splenocytes from such vaccinated mice into lymphodepleted recipient mice. The transferred tumor-specific T cells proliferate in these “empty” mice at a 30-fold excess over that in normal non-depleted recipients. The lymphodepleted recipients of adoptive transfer were completely protected against challenge with the lymphoma tumor at a 100-fold greater tumor cell dose than that required to kill normal animals. Because the transferred effector lymphocytes may still be contaminated by the same immuno-regulatory elements (e.g. Tregs) present in the donor mice, we asked whether these might proliferate and diminish the effector function of anti-tumor T cells. By tracking the homeostatic proliferation of the transferred cells we observed an apparent preferential proliferative capacity of the tumor-responsive CD8 cells and a relative decreased proliferative capacity of transferred foxP3(+) Treg cells. These data suggest that the post-transplant environment can skew the relative proportion of different T cell subsets, which may be a central mechanism for the dramatic improvement in tumor protection observed.