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.
Department of Microbiology and Immunology, University of Nevada, Reno, Nevada 89557, USA.
Lisbeth A
LA
Welniak
Lynnette
L
Shorts
Jeff
J
Subleski
Bruce R
BR
Blazar
Robert H
RH
Wiltrout
William J
WJ
Murphy
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation / Q000276:immunology; D019013:CD40 Antigens / Q000032:analysis / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D018572:Disease-Free Survival; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D016130:Immunophenotyping; D007376:Interleukin-2 / Q000494:pharmacology / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015996:Survival Rate
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D007376:Interleukin-2