Tumor regression by anti-CD40 and interleukin-2: Role of CD40 in hematopoietic cells and organ-specific effects

CD40 stimulation can synergize with interleukin (IL)-2 for antitumor responses against mouse metastatic renal cell carcinomas, with coincident increases in tumor-specific CD8⁺ T-cell responses and dendritic cell numbers in both the spleen and liver. Because CD40 is present on various hematopoietic-derived cells, endothelial cells, and some tumors themselves, this study was performed to determine whether the antitumor effects of CD40 stimulation and IL-2 were primarily mediated by CD40⁺ hematopoietic-derived cells. Bone marrow chimeras were created by reconstituting lethally irradiated CD40^+/+ recipients with bone marrow from CD40^-/- or CD40^+/+ mice. Chimeric mice were then implanted orthotopically with renal cancer cells, followed by treatment with anti-CD40 agonist monoclonal antibodies and IL-2. Immune parameters of the spleen and liver were assessed after therapy and correlated with antitumor responses. The antitumor effects in the CD40^-/- bone marrow transplantation chimeras were almost completely abrogated after treatment, and this shows that hematopoietically derived CD40⁺ cells are the principal targets for CD40 stimulation in this model. Although both spleen and liver showed reductions in CD8⁺ T-cell and dendritic cell expansion in the CD40^-/- versus CD40^+/+ chimeras after therapy, only the liver exhibited no significant increases in either CD8⁺ T cells or dendritic cells after treatment. CD40 cells on hematopoietic cells are the primary target for anti-CD40 and IL-2 therapy. The results also suggest that the immunologic events in the liver may be more revealing that those in lymphoid organs with regard to critical events related to responses after therapy.