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Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40

Abstract

Tumor antigen-specific T-cell tolerance limits the efficacy of therapeutic cancer vaccines. Antigen-presenting cells mediate the induction of T-cell tolerance to self-antigens. We therefore assessed the fate of tumor-specific CD4+ T cells in tumor-bearing recipients after in vivo activation of antigen-presenting cells with antibodies against CD40. Such treatment not only preserved the responsiveness of this population, but resulted in their endogenous activation. Established tumors regressed in vaccinated mice treated with antibody against CD40 at a time when no response was achieved with vaccination alone. These results indicate that modulation of antigen-presenting cells may be a useful strategy for enhancing responsiveness to immunization.

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Figure 1: Effect of CD40 ligation on the responsiveness of RencaHA bearing mice to vaccination.
Figure 2: Effect of in vivo ligation of CD40 on the functional responses of antigen-specific CD4+T cells.
Figure 3: Analysis of HA-specific T cells isolated from regional lymph nodes.
Figure 4: Effect of CD40 ligation on the anti-tumor response to vaccination.
Figure 5: Effect of CD40 ligation on the response to intravenous HA peptide.
Figure 6: Experimental protocols.

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Acknowledgements

The authors thank S. Cooke for technical assistance, and D. Pardoll, A. Adler and E. Fuchs for discussions and review of the manuscript. This work was supported by a gift from the Hanford family, and by PHS grants RO1 CA78658 and CA078656. E.M.S. is a Fellow of the Lymphoma Research Foundation of America. I.B. is a Fellow of the Leukemia Society of America and H.I.L. is a Scholar of the Leukemia Society of America.

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Sotomayor, E., Borrello, I., Tubb, E. et al. Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40. Nat Med 5, 780–787 (1999). https://doi.org/10.1038/10503

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