Blockade of transforming growth factor-β signaling in tumor-reactive CD8+ T cells activates the antitumor immune response cycle

Qiang Zhang, Ximing J. Yang, Shilajit D. Kundu, Michael Pins, Borko Javonovic, Robert Meyer, Seong Jin Kim, Norman M. Greenberg, Timothy Kuzel, Richard Meagher, Yinglu Guo, Chung Lee*

*Corresponding author for this work

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Transforming growth factor-β (TGF-β) is a potent immunosuppressant. Overproduction of TGF-β by tumor cells leads to evasion of host immune surveillance and tumor progression. Results of our early studies showed that adoptive transfer of tumor-reactive, TGF-β-insensitive CD8+ T cells into immunocompetent mice was able to eradicate lung metastasis of mouse prostate cancer. The present study was conducted with three objectives. (a) We tested if this technology could be applied to the treatment of solid xenograft tumors in allogeneic immunodeficient hosts. (b) We determined relevant variables in the tumor microenvironment with the treatment. (c) We tested if immune cells other than CD8+ T cells were required for the antitumor effect. Mouse prostate cancer cells, TRAMP-C2 of the C57BL/6 strain, grown in immunodeficient allogeneic hosts of BALB/c strain, were used as a xenograft model. Tumor-reactive CD8+ T cells from C57BL/6 mice were isolated, expanded ex vivo, and rendered insensitive to TGF-β by introducing a dominant-negative TGF-β type II receptor vector. Seven days following s.c. injection of TRAMP-C2 cells (5 × 105) into the flank of male BALB/c-Rag1-/- mice, tumor-reactive, TGF-β-insensitive CD8+ T cells (1.5 × 107) were transferred with and without the cotransfer of an equal number of CD8-depleted splenocytes from C57BL/6 donors. Naive CD8+ T cells or green fluorescent protein-empty vector-transfected tumor-reactive CD8+ T cells were transferred as controls. Forty days following the transfer, the average tumor weight in animals that received cotransfer of tumor-reactive, TGF-β-insensitive CD8+ T cells and CD8-depleted splenocytes was at least 50% less than that in animals of all other groups (P < 0.05). Tumors in animals of the former group showed a massive infiltration of CD8+ T cells. This was associated with secretion of relevant cytokines, decreased tumor proliferation, reduced angiogenesis, and increased tumor apoptosis. Based on these results, we postulated a concept of antitumor immune response cycle in tumor immunology.

Original languageEnglish (US)
Pages (from-to)1733-1743
Number of pages11
JournalMolecular Cancer Therapeutics
Volume5
Issue number7
DOIs
StatePublished - Jul 1 2006

Fingerprint

Transforming Growth Factors
T-Lymphocytes
Neoplasms
Heterografts
Prostatic Neoplasms
Immune Evasion
Tumor Microenvironment
Growth Factor Receptors
Adoptive Transfer
Immunosuppressive Agents
Green Fluorescent Proteins
Allergy and Immunology
Tumor Burden
Inbred C57BL Mouse
Apoptosis
Cytokines
Neoplasm Metastasis
Technology

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Zhang, Qiang ; Yang, Ximing J. ; Kundu, Shilajit D. ; Pins, Michael ; Javonovic, Borko ; Meyer, Robert ; Kim, Seong Jin ; Greenberg, Norman M. ; Kuzel, Timothy ; Meagher, Richard ; Guo, Yinglu ; Lee, Chung. / Blockade of transforming growth factor-β signaling in tumor-reactive CD8+ T cells activates the antitumor immune response cycle. In: Molecular Cancer Therapeutics. 2006 ; Vol. 5, No. 7. pp. 1733-1743.
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abstract = "Transforming growth factor-β (TGF-β) is a potent immunosuppressant. Overproduction of TGF-β by tumor cells leads to evasion of host immune surveillance and tumor progression. Results of our early studies showed that adoptive transfer of tumor-reactive, TGF-β-insensitive CD8+ T cells into immunocompetent mice was able to eradicate lung metastasis of mouse prostate cancer. The present study was conducted with three objectives. (a) We tested if this technology could be applied to the treatment of solid xenograft tumors in allogeneic immunodeficient hosts. (b) We determined relevant variables in the tumor microenvironment with the treatment. (c) We tested if immune cells other than CD8+ T cells were required for the antitumor effect. Mouse prostate cancer cells, TRAMP-C2 of the C57BL/6 strain, grown in immunodeficient allogeneic hosts of BALB/c strain, were used as a xenograft model. Tumor-reactive CD8+ T cells from C57BL/6 mice were isolated, expanded ex vivo, and rendered insensitive to TGF-β by introducing a dominant-negative TGF-β type II receptor vector. Seven days following s.c. injection of TRAMP-C2 cells (5 × 105) into the flank of male BALB/c-Rag1-/- mice, tumor-reactive, TGF-β-insensitive CD8+ T cells (1.5 × 107) were transferred with and without the cotransfer of an equal number of CD8-depleted splenocytes from C57BL/6 donors. Naive CD8+ T cells or green fluorescent protein-empty vector-transfected tumor-reactive CD8+ T cells were transferred as controls. Forty days following the transfer, the average tumor weight in animals that received cotransfer of tumor-reactive, TGF-β-insensitive CD8+ T cells and CD8-depleted splenocytes was at least 50{\%} less than that in animals of all other groups (P < 0.05). Tumors in animals of the former group showed a massive infiltration of CD8+ T cells. This was associated with secretion of relevant cytokines, decreased tumor proliferation, reduced angiogenesis, and increased tumor apoptosis. Based on these results, we postulated a concept of antitumor immune response cycle in tumor immunology.",
author = "Qiang Zhang and Yang, {Ximing J.} and Kundu, {Shilajit D.} and Michael Pins and Borko Javonovic and Robert Meyer and Kim, {Seong Jin} and Greenberg, {Norman M.} and Timothy Kuzel and Richard Meagher and Yinglu Guo and Chung Lee",
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Blockade of transforming growth factor-β signaling in tumor-reactive CD8+ T cells activates the antitumor immune response cycle. / Zhang, Qiang; Yang, Ximing J.; Kundu, Shilajit D.; Pins, Michael; Javonovic, Borko; Meyer, Robert; Kim, Seong Jin; Greenberg, Norman M.; Kuzel, Timothy; Meagher, Richard; Guo, Yinglu; Lee, Chung.

In: Molecular Cancer Therapeutics, Vol. 5, No. 7, 01.07.2006, p. 1733-1743.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Blockade of transforming growth factor-β signaling in tumor-reactive CD8+ T cells activates the antitumor immune response cycle

AU - Zhang, Qiang

AU - Yang, Ximing J.

AU - Kundu, Shilajit D.

AU - Pins, Michael

AU - Javonovic, Borko

AU - Meyer, Robert

AU - Kim, Seong Jin

AU - Greenberg, Norman M.

AU - Kuzel, Timothy

AU - Meagher, Richard

AU - Guo, Yinglu

AU - Lee, Chung

PY - 2006/7/1

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N2 - Transforming growth factor-β (TGF-β) is a potent immunosuppressant. Overproduction of TGF-β by tumor cells leads to evasion of host immune surveillance and tumor progression. Results of our early studies showed that adoptive transfer of tumor-reactive, TGF-β-insensitive CD8+ T cells into immunocompetent mice was able to eradicate lung metastasis of mouse prostate cancer. The present study was conducted with three objectives. (a) We tested if this technology could be applied to the treatment of solid xenograft tumors in allogeneic immunodeficient hosts. (b) We determined relevant variables in the tumor microenvironment with the treatment. (c) We tested if immune cells other than CD8+ T cells were required for the antitumor effect. Mouse prostate cancer cells, TRAMP-C2 of the C57BL/6 strain, grown in immunodeficient allogeneic hosts of BALB/c strain, were used as a xenograft model. Tumor-reactive CD8+ T cells from C57BL/6 mice were isolated, expanded ex vivo, and rendered insensitive to TGF-β by introducing a dominant-negative TGF-β type II receptor vector. Seven days following s.c. injection of TRAMP-C2 cells (5 × 105) into the flank of male BALB/c-Rag1-/- mice, tumor-reactive, TGF-β-insensitive CD8+ T cells (1.5 × 107) were transferred with and without the cotransfer of an equal number of CD8-depleted splenocytes from C57BL/6 donors. Naive CD8+ T cells or green fluorescent protein-empty vector-transfected tumor-reactive CD8+ T cells were transferred as controls. Forty days following the transfer, the average tumor weight in animals that received cotransfer of tumor-reactive, TGF-β-insensitive CD8+ T cells and CD8-depleted splenocytes was at least 50% less than that in animals of all other groups (P < 0.05). Tumors in animals of the former group showed a massive infiltration of CD8+ T cells. This was associated with secretion of relevant cytokines, decreased tumor proliferation, reduced angiogenesis, and increased tumor apoptosis. Based on these results, we postulated a concept of antitumor immune response cycle in tumor immunology.

AB - Transforming growth factor-β (TGF-β) is a potent immunosuppressant. Overproduction of TGF-β by tumor cells leads to evasion of host immune surveillance and tumor progression. Results of our early studies showed that adoptive transfer of tumor-reactive, TGF-β-insensitive CD8+ T cells into immunocompetent mice was able to eradicate lung metastasis of mouse prostate cancer. The present study was conducted with three objectives. (a) We tested if this technology could be applied to the treatment of solid xenograft tumors in allogeneic immunodeficient hosts. (b) We determined relevant variables in the tumor microenvironment with the treatment. (c) We tested if immune cells other than CD8+ T cells were required for the antitumor effect. Mouse prostate cancer cells, TRAMP-C2 of the C57BL/6 strain, grown in immunodeficient allogeneic hosts of BALB/c strain, were used as a xenograft model. Tumor-reactive CD8+ T cells from C57BL/6 mice were isolated, expanded ex vivo, and rendered insensitive to TGF-β by introducing a dominant-negative TGF-β type II receptor vector. Seven days following s.c. injection of TRAMP-C2 cells (5 × 105) into the flank of male BALB/c-Rag1-/- mice, tumor-reactive, TGF-β-insensitive CD8+ T cells (1.5 × 107) were transferred with and without the cotransfer of an equal number of CD8-depleted splenocytes from C57BL/6 donors. Naive CD8+ T cells or green fluorescent protein-empty vector-transfected tumor-reactive CD8+ T cells were transferred as controls. Forty days following the transfer, the average tumor weight in animals that received cotransfer of tumor-reactive, TGF-β-insensitive CD8+ T cells and CD8-depleted splenocytes was at least 50% less than that in animals of all other groups (P < 0.05). Tumors in animals of the former group showed a massive infiltration of CD8+ T cells. This was associated with secretion of relevant cytokines, decreased tumor proliferation, reduced angiogenesis, and increased tumor apoptosis. Based on these results, we postulated a concept of antitumor immune response cycle in tumor immunology.

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