title: Anti-VEGF antibody enhances the antitumor effect of CD40.
abstract: As its central immunomodulatory effects, CD40 induces interleukin (IL)-12-dependent antitumor immune responses; as its local protumor effects, CD40 induces the expression of vascular endothelial growth factor (VEGF) that promotes tumor angiogenesis and growth. Therefore, using a previously established tumor model in mouse, we examined if the antitumor functions of CD40 are self-limited by VEGF induction. We observed that as the tumor mass grew during day 6 to day 18, VEGF expression in the tumor peaked with concomitant decrease in expressions of CD40 and IL-12 but not of IL-10. Among the angiogenic factors, VEGF-B, VEGFR-1, VEGFR-2, angiopoietin-1 and Tie2 expressions decreased, whereas the expressions of angiopoietin-2 and angiopoietin-3 increased with tumor growth. As significant changes in the expressions of these factors were observed on day 6, we treated the tumor-bearing mice with the agonistic anti-CD40 antibody or neutralizing anti-VEGF antibody-alone or in combination-from the fifth day after the injection of tumor cells. The anti-VEGF antibody significantly enhanced the antitumor effects of the anti-CD40 antibody, as observed through increased survival of the mice, accompanied by reduced angiogenesis and angiopoietin-2 expression but higher T-cell proliferation in response to tumor antigens, increased interferon-γ production and tumor cell cytotoxicity and higher levels of tumor antigen-specific serum IgM, IgG1 and IgG2a, indicating B-cell activation. Thus, our data show for the first time that the combined treatment with an agonistic anti-CD40 antibody and a neutralizing anti-VEGF antibody, which increases antitumor immune response or reduces local angiogenesis, respectively, is a novel antitumor strategy.
authors.affiliation: National Centre for Cell Science, Ganeshkhind, Pune, India.
authors.forename: Sathishkumar
authors.initials: S
authors.lastname: Selvaraj
authors.forename: Mahesh
authors.initials: M
authors.lastname: Raundhal
authors.forename: Ashok
authors.initials: A
authors.lastname: Patidar
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Saha
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D019013:CD40 Antigens / Q000037:antagonists & inhibitors* / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000906:Antibodies; D019013:CD40 Antigens; D042461:Vascular Endothelial Growth Factor A; D007371:Interferon-gamma
keywords: CD40; VEGF; antitumor immunity; cytotoxic T cells