Cancer Immunology, Immunotherapy

, Volume 57, Issue 8, pp 1151–1160 | Cite as

CD40 ligation in vivo can induce T cell independent antitumor effects even against immunogenic tumors

  • Alexander L. Rakhmilevich
  • Ilia N. Buhtoiarov
  • Miroslav Malkovsky
  • Paul M. Sondel
Original Article

Abstract

Antitumor effects of CD40 ligation appear to involve distinct antitumor effector cells in different experimental models. In this study, we tested whether T cells were required for antitumor effects of agonistic anti-CD40 mAb (αCD40) against immunogenic versus poorly immunogenic tumors. Treatment of mice bearing poorly immunogenic B16 melanoma and its more immunogenic variant, B16-hsp72.1, with αCD40 resulted in a similar level of tumor growth suppression. Depletion of T cells did not reduce the antitumor effects in these 2 tumor models. To generate antitumor T cell responses, C57BL/6 mice were immunized with irradiated B16-hsp72.1. Treatment of these vaccinated mice challenged with a high dose of B16-hsp72.1 tumor cells with αCD40 induced tumor growth suppression, which was reduced by T-cell depletion, demonstrating that T cells were involved in the antitumor effect of αCD40. However, immunized mice depleted of T cells and treated with αCD40 were still able to suppress tumor growth as compared to tumor growth in immunized, T cell-depleted mice not treated with αCD40, suggesting that T cells were not required for the antitumor effect of αCD40. To confirm a lack of correlation between tumor immunogenicity and T-cell requirement in antitumor effects of CD40 ligation, we found that αCD40 induced tumor growth suppression in nude and SCID/beige mice bearing highly immunogenic tumors such as Meth A sarcoma, suggesting that macrophages may play a role. Indeed, both poorly immunogenic and highly immunogenic tumors were sensitive to in vitro growth inhibition by macrophages from αCD40-treated mice. Taken together, our results indicate that antitumor effects induced by αCD40, even against immunogenic tumors, can be observed in the absence of T cells and may involve macrophages.

Keywords

Tumor Immunity T cells Monocytes/macrophages Anti-CD40 mAb 

Abbreviations

CD40L

CD40 ligand

αCD40

Anti-CD40 monoclonal antibody

Macrophages

PEC

Peritoneal exudate cells

IgG

Immunoglobulin G

3H-TdR

3H-thymidine

Notes

Acknowledgments

The authors thank Drs. Jackie Hank, Jacek Gan, and Hillary Lum for helpful discussions.

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Alexander L. Rakhmilevich
    • 1
    • 4
  • Ilia N. Buhtoiarov
    • 1
    • 4
  • Miroslav Malkovsky
    • 2
    • 4
  • Paul M. Sondel
    • 1
    • 3
    • 4
  1. 1.The Department of Human OncologyUniversity of Wisconsin, K4/413 Clinical Science CenterMadisonUSA
  2. 2.Department of Medical Microbiology and ImmunologyUniversity of Wisconsin, K4/448 Clinical Science CenterMadisonUSA
  3. 3.Department of PediatricsUniversity of Wisconsin, K4/448 Clinical Science CenterMadisonUSA
  4. 4.The UW Comprehensive Cancer Center University of Wisconsin, K4/448 Clinical Science CenterMadisonUSA

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