Enhanced responses to tumor immunization following total body irradiation are time-dependent

Adi Diab, Robert R. Jenq, Gabrielle A. Rizzuto, Adam D. Cohen, Deonka W. Huggins, Taha Merghoub, Manuel E. Engelhorn, José A. Guevara-Patiño, David Suh, Vanessa M. Hubbard-Lucey, Adam A. Kochman, Suzie Chen, Hong Zhong, Jedd D. Wolchok, Marcel R.M. Van Den Brink, Alan N. Houghton, Miguel Angel Perales

Research output: Contribution to journalArticle

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Abstract

The development of successful cancer vaccines is contingent on the ability to induce effective and persistent anti-tumor immunity against self-antigens that do not typically elicit immune responses. In this study, we examine the effects of a non-myeloablative dose of total body irradiation on the ability of tumor-naïve mice to respond to DNA vaccines against melanoma. We demonstrate that irradiation followed by lymphocyte infusion results in a dramatic increase in responsiveness to tumor vaccination, with augmentation of T cell responses to tumor antigens and tumor eradication. In irradiated mice, infused CD8+ T cells expand in an environment that is relatively depleted in regulatory T cells, and this correlates with improved CD8 + T cell functionality. We also observe an increase in the frequency of dendritic cells displaying an activated phenotype within lymphoid organs in the first 24 hours after irradiation. Intriguingly, both the relative decrease in regulatory T cells and increase in activated dendritic cells correspond with a brief window of augmented responsiveness to immunization. After this 24 hour window, the numbers of dendritic cells decline, as does the ability of mice to respond to immunizations. When immunizations are initiated within the period of augmented dendritic cell activation, mice develop anti-tumor responses that show increased durability as well as magnitude, and this approach leads to improved survival in experiments with mice bearing established tumors as well as in a spontaneous melanoma model. We conclude that irradiation can produce potent immune adjuvant effects independent of its ability to induce tumor ablation, and that the timing of immunization and lymphocyte infusion in the irradiated host are crucial for generating optimal anti-tumor immunity. Clinical strategies using these approaches must therefore optimize such parameters, as the correct timing of infusion and vaccination may mean the difference between an ineffective treatment and successful tumor eradication.

Original languageEnglish (US)
Article numbere82496
JournalPloS one
Volume8
Issue number12
DOIs
StatePublished - Dec 12 2013

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Immunization
Whole-Body Irradiation
Tumors
immunization
irradiation
Irradiation
T-cells
neoplasms
Neoplasms
Dendritic Cells
dendritic cells
T-lymphocytes
Lymphocytes
mice
Regulatory T-Lymphocytes
T-Lymphocytes
melanoma
Immunity
Melanoma
Vaccination

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Diab, A., Jenq, R. R., Rizzuto, G. A., Cohen, A. D., Huggins, D. W., Merghoub, T., ... Perales, M. A. (2013). Enhanced responses to tumor immunization following total body irradiation are time-dependent. PloS one, 8(12), [e82496]. https://doi.org/10.1371/journal.pone.0082496
Diab, Adi ; Jenq, Robert R. ; Rizzuto, Gabrielle A. ; Cohen, Adam D. ; Huggins, Deonka W. ; Merghoub, Taha ; Engelhorn, Manuel E. ; Guevara-Patiño, José A. ; Suh, David ; Hubbard-Lucey, Vanessa M. ; Kochman, Adam A. ; Chen, Suzie ; Zhong, Hong ; Wolchok, Jedd D. ; Van Den Brink, Marcel R.M. ; Houghton, Alan N. ; Perales, Miguel Angel. / Enhanced responses to tumor immunization following total body irradiation are time-dependent. In: PloS one. 2013 ; Vol. 8, No. 12.
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abstract = "The development of successful cancer vaccines is contingent on the ability to induce effective and persistent anti-tumor immunity against self-antigens that do not typically elicit immune responses. In this study, we examine the effects of a non-myeloablative dose of total body irradiation on the ability of tumor-na{\"i}ve mice to respond to DNA vaccines against melanoma. We demonstrate that irradiation followed by lymphocyte infusion results in a dramatic increase in responsiveness to tumor vaccination, with augmentation of T cell responses to tumor antigens and tumor eradication. In irradiated mice, infused CD8+ T cells expand in an environment that is relatively depleted in regulatory T cells, and this correlates with improved CD8 + T cell functionality. We also observe an increase in the frequency of dendritic cells displaying an activated phenotype within lymphoid organs in the first 24 hours after irradiation. Intriguingly, both the relative decrease in regulatory T cells and increase in activated dendritic cells correspond with a brief window of augmented responsiveness to immunization. After this 24 hour window, the numbers of dendritic cells decline, as does the ability of mice to respond to immunizations. When immunizations are initiated within the period of augmented dendritic cell activation, mice develop anti-tumor responses that show increased durability as well as magnitude, and this approach leads to improved survival in experiments with mice bearing established tumors as well as in a spontaneous melanoma model. We conclude that irradiation can produce potent immune adjuvant effects independent of its ability to induce tumor ablation, and that the timing of immunization and lymphocyte infusion in the irradiated host are crucial for generating optimal anti-tumor immunity. Clinical strategies using these approaches must therefore optimize such parameters, as the correct timing of infusion and vaccination may mean the difference between an ineffective treatment and successful tumor eradication.",
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Diab, A, Jenq, RR, Rizzuto, GA, Cohen, AD, Huggins, DW, Merghoub, T, Engelhorn, ME, Guevara-Patiño, JA, Suh, D, Hubbard-Lucey, VM, Kochman, AA, Chen, S, Zhong, H, Wolchok, JD, Van Den Brink, MRM, Houghton, AN & Perales, MA 2013, 'Enhanced responses to tumor immunization following total body irradiation are time-dependent', PloS one, vol. 8, no. 12, e82496. https://doi.org/10.1371/journal.pone.0082496

Enhanced responses to tumor immunization following total body irradiation are time-dependent. / Diab, Adi; Jenq, Robert R.; Rizzuto, Gabrielle A.; Cohen, Adam D.; Huggins, Deonka W.; Merghoub, Taha; Engelhorn, Manuel E.; Guevara-Patiño, José A.; Suh, David; Hubbard-Lucey, Vanessa M.; Kochman, Adam A.; Chen, Suzie; Zhong, Hong; Wolchok, Jedd D.; Van Den Brink, Marcel R.M.; Houghton, Alan N.; Perales, Miguel Angel.

In: PloS one, Vol. 8, No. 12, e82496, 12.12.2013.

Research output: Contribution to journalArticle

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AU - Diab, Adi

AU - Jenq, Robert R.

AU - Rizzuto, Gabrielle A.

AU - Cohen, Adam D.

AU - Huggins, Deonka W.

AU - Merghoub, Taha

AU - Engelhorn, Manuel E.

AU - Guevara-Patiño, José A.

AU - Suh, David

AU - Hubbard-Lucey, Vanessa M.

AU - Kochman, Adam A.

AU - Chen, Suzie

AU - Zhong, Hong

AU - Wolchok, Jedd D.

AU - Van Den Brink, Marcel R.M.

AU - Houghton, Alan N.

AU - Perales, Miguel Angel

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N2 - The development of successful cancer vaccines is contingent on the ability to induce effective and persistent anti-tumor immunity against self-antigens that do not typically elicit immune responses. In this study, we examine the effects of a non-myeloablative dose of total body irradiation on the ability of tumor-naïve mice to respond to DNA vaccines against melanoma. We demonstrate that irradiation followed by lymphocyte infusion results in a dramatic increase in responsiveness to tumor vaccination, with augmentation of T cell responses to tumor antigens and tumor eradication. In irradiated mice, infused CD8+ T cells expand in an environment that is relatively depleted in regulatory T cells, and this correlates with improved CD8 + T cell functionality. We also observe an increase in the frequency of dendritic cells displaying an activated phenotype within lymphoid organs in the first 24 hours after irradiation. Intriguingly, both the relative decrease in regulatory T cells and increase in activated dendritic cells correspond with a brief window of augmented responsiveness to immunization. After this 24 hour window, the numbers of dendritic cells decline, as does the ability of mice to respond to immunizations. When immunizations are initiated within the period of augmented dendritic cell activation, mice develop anti-tumor responses that show increased durability as well as magnitude, and this approach leads to improved survival in experiments with mice bearing established tumors as well as in a spontaneous melanoma model. We conclude that irradiation can produce potent immune adjuvant effects independent of its ability to induce tumor ablation, and that the timing of immunization and lymphocyte infusion in the irradiated host are crucial for generating optimal anti-tumor immunity. Clinical strategies using these approaches must therefore optimize such parameters, as the correct timing of infusion and vaccination may mean the difference between an ineffective treatment and successful tumor eradication.

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Diab A, Jenq RR, Rizzuto GA, Cohen AD, Huggins DW, Merghoub T et al. Enhanced responses to tumor immunization following total body irradiation are time-dependent. PloS one. 2013 Dec 12;8(12). e82496. https://doi.org/10.1371/journal.pone.0082496