CD40 stimulation leads to effective therapy of CD40- tumors through induction of strong systemic cytotoxic T lymphocyte immunity

Geertje J. D. van Mierlo, Annemieke Th. Den Boer, Jan Paul Medema, Ellen I. H. van der Voort, Marieke F. Fransen, Rienk Offringa, Cornelis J. M. Melief, Rene E. M. Toes

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Adequate spontaneous activation of tumor-specific T lymphocytes in tumor-bearing hosts is rare, despite the expression of tumor antigens that are potentially highly immunogenic. For example, failure of the immune system to raise competent responses against established tumors expressing the human adenovirus E1A-antigen allows this tumor to grow in immunocompetent mice. We show that systemic in vivo administration of agonistic anti-CD40 anti- bodies into tumor-bearing mice results in tumor eradication mediated by CD8+ T cells. Treatment resulted in a strong expansion and systemic accumulation of E1A-specific CTL and depended on CD40 expression on host cells, as the tumor was CD40-, and therapy failed in CD40-deficient mice. Local intratumoral administration of anti-CD40 mAb is equally effective in licensing strong, systemic CTL immunity, resulting in the clearance of distant tumor nodules. Our data indicate that the immune response after cancer-host interactions can be directed toward competence, leading to the cure of established tumors merely by delivery of a CD40-dependent "license to kill" signal.
Original languageEnglish
Pages (from-to)5561-5566
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number8
DOIs
Publication statusPublished - 2002
Externally publishedYes

Cite this

van Mierlo, Geertje J. D. ; Boer, Annemieke Th. Den ; Medema, Jan Paul ; van der Voort, Ellen I. H. ; Fransen, Marieke F. ; Offringa, Rienk ; Melief, Cornelis J. M. ; Toes, Rene E. M. / CD40 stimulation leads to effective therapy of CD40- tumors through induction of strong systemic cytotoxic T lymphocyte immunity. In: Proceedings of the National Academy of Sciences of the United States of America. 2002 ; Vol. 99, No. 8. pp. 5561-5566.
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title = "CD40 stimulation leads to effective therapy of CD40- tumors through induction of strong systemic cytotoxic T lymphocyte immunity",
abstract = "Adequate spontaneous activation of tumor-specific T lymphocytes in tumor-bearing hosts is rare, despite the expression of tumor antigens that are potentially highly immunogenic. For example, failure of the immune system to raise competent responses against established tumors expressing the human adenovirus E1A-antigen allows this tumor to grow in immunocompetent mice. We show that systemic in vivo administration of agonistic anti-CD40 anti- bodies into tumor-bearing mice results in tumor eradication mediated by CD8+ T cells. Treatment resulted in a strong expansion and systemic accumulation of E1A-specific CTL and depended on CD40 expression on host cells, as the tumor was CD40-, and therapy failed in CD40-deficient mice. Local intratumoral administration of anti-CD40 mAb is equally effective in licensing strong, systemic CTL immunity, resulting in the clearance of distant tumor nodules. Our data indicate that the immune response after cancer-host interactions can be directed toward competence, leading to the cure of established tumors merely by delivery of a CD40-dependent {"}license to kill{"} signal.",
author = "{van Mierlo}, {Geertje J. D.} and Boer, {Annemieke Th. Den} and Medema, {Jan Paul} and {van der Voort}, {Ellen I. H.} and Fransen, {Marieke F.} and Rienk Offringa and Melief, {Cornelis J. M.} and Toes, {Rene E. M.}",
year = "2002",
doi = "10.1073/pnas.082107699",
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volume = "99",
pages = "5561--5566",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
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CD40 stimulation leads to effective therapy of CD40- tumors through induction of strong systemic cytotoxic T lymphocyte immunity. / van Mierlo, Geertje J. D.; Boer, Annemieke Th. Den; Medema, Jan Paul; van der Voort, Ellen I. H.; Fransen, Marieke F.; Offringa, Rienk; Melief, Cornelis J. M.; Toes, Rene E. M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 8, 2002, p. 5561-5566.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - van Mierlo, Geertje J. D.

AU - Boer, Annemieke Th. Den

AU - Medema, Jan Paul

AU - van der Voort, Ellen I. H.

AU - Fransen, Marieke F.

AU - Offringa, Rienk

AU - Melief, Cornelis J. M.

AU - Toes, Rene E. M.

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AB - Adequate spontaneous activation of tumor-specific T lymphocytes in tumor-bearing hosts is rare, despite the expression of tumor antigens that are potentially highly immunogenic. For example, failure of the immune system to raise competent responses against established tumors expressing the human adenovirus E1A-antigen allows this tumor to grow in immunocompetent mice. We show that systemic in vivo administration of agonistic anti-CD40 anti- bodies into tumor-bearing mice results in tumor eradication mediated by CD8+ T cells. Treatment resulted in a strong expansion and systemic accumulation of E1A-specific CTL and depended on CD40 expression on host cells, as the tumor was CD40-, and therapy failed in CD40-deficient mice. Local intratumoral administration of anti-CD40 mAb is equally effective in licensing strong, systemic CTL immunity, resulting in the clearance of distant tumor nodules. Our data indicate that the immune response after cancer-host interactions can be directed toward competence, leading to the cure of established tumors merely by delivery of a CD40-dependent "license to kill" signal.

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