| Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) is a crucial inhibitory molecule to restrain T cell functions. CTLA-4 blockade with a monoclonal antibody (anti-CTLA-4) induces anti-tumor responses in a subset of patients and has been approved by the FDA as standard therapy for melanoma. We recently identified inducible costimulator (ICOS) as a crucial player in the antitumor effects of CTLA-4 blockade. We now show that concomitant CTLA-4 blockade plus ICOS engagement by tumor cell vaccines engineered to express ICOS-ligand enhanced anti-tumor immune responses in both quantity and quality and significantly improved rejection of established melanoma and prostate cancer in mice. This study provides strong evidence to support future combinatorial approaches incorporating anti-CTLA-4 plus ICOS engagement in the clinic.;We explored another strategy to enhance anti-tumor response by targeting the migration of regulatory T cells into the tumor. We proposed certain chemokines and their cognate receptors play key roles in this process. Chemokine receptors CCR4 and CCR8 are preferentially expressed by regulatory T cells in the tumor where their ligands CCL1 and CCL17 are upregulated. CCL17 was able to induce specific migration of regulatory T cells from tumor-bearing mice, and we identified a CD11b+ F4/80+ Gr-1- population in the tumor as the major source of CCL17. With an in vivo migration assay and a bone marrow chimera model, we demonstrated that CCR4 is required for the migration of regulatory T cells to the vaccine site.;Lastly, we found that transfer of small numbers of naive tumor-reactive CD4 T cells into lymphopenic recipients induces substantial T cell expansion, differentiation, and regression of large established tumors without the need for in vitro manipulation. Surprisingly, CD4 T cells developed cytotoxic activity, and tumor rejection was dependent on class II-restricted recognition of tumors by tumor-reactive CD4 T cells. Furthermore, blockade of the CTLA-4 on transferred CD4 T cells resulted in greater expansion of effector T cells, diminished accumulation of regulatory T cells, and superior antitumor activity. These findings suggest a novel potential therapeutic role for cytotoxic CD4 T cells and CTLA-4 blockade in cancer immunotherapy, and the potential advantages of differentiating tumor-reactive CD4 cells in vivo. |
