Infiltration of tumor-reactive transforming growth factor-beta insensitive CD8+ T cells into the tumor parenchyma is associated with apoptosis and rejection of tumor cells

Qiang Zhang, Thomas L. Jang, Ximing Yang, Irwin Park, Robert E. Meyer, Shilajit Kundu, Michael Pins, Borko Javonovic, Timothy Kuzel, Seong Jin Kim, Luk Van Parijs, Norm Smith, Larry Wong, Norman M. Greenberg, Yinglu Guo, Chung Lee*

*Corresponding author for this work

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

BACKGROUND. TGF-β is a potent immunosuppressant. High levels of TGF-β produced by cancer cells have a negative inhibition effect on surrounding host immune cells and leads to evasion of the host immune surveillance and tumor progression. In the present study, we report a distinct ability of tumor reactive, TGF-β-insensitive CD8+ T cells to infiltrate into established tumors, secrete relevant cytokines, and induce apoptosis of tumor cells. METHODS. CD8+ T cells were isolated from the spleens of C57BL/6 mice, which were primed with irradiated mouse prostate cancer cells, the TRAMP-C2 cells. After ex vivo expansion, these tumor reactive CD8+ cells were rendered TGF-β-insensitive by infection with a retroviral (MSCV)-mediated dominant negative TGF-β type II receptor (TβRIIDN). Control CD8+ cells consist of those transfected with the GFP-only empty vector and naïve CD8+ T cells. Recipient mice were challenged with a single injection of TRAMP-C2 cells 21 days before adoptive transfer of CD8+ T cells was performed. Forty days after the adoptive transfer, all animals were sacrificed. The presence of pulmonary metastases was evaluated pathologically. Serial slides of malignant tissues were used for immunofluorescent staining for different kinds of immune cell infiltration, cytokines, and apoptosis analysis. RESULTS. Pulmonary metastases were either eliminated or significantly reduced in the group receiving adoptive transfer of tumor-reactive TGF-β-insensitive CD8+ T cells (3 out of 12) when compared to GFP controls (9 out of 12), and naïve CD8 + T cells (12 out of 12). Results of immunofluorescent studies demonstrated that only tumor-reactive TGF-β-insensitive CD8+ T cells were able to infiltrate into the tumor and mediate apoptosis when compared to CD4+ T cells, NK cells, and B cells. A large amount of cytokines such as perform, nitric oxide, IFN-γ, IL-2, TNF-α were secreted in tumor tissue treated with tumor-reactive TGF-β-insensitive CD8+ T cells. No immune cells infiltration and cytokine secretion were detected in tumor tissues treated with naïve T cells and GFP controls. CONCLUSIONS. Our results demonstrate the mechanism of anti-tumor effect of tumor-reactive TGF-β-insensitive CD8+ T cells that adoptive transfer of these CD8+ T cells resulted in infiltration of these immune cells into the tumor parenchyma, secretion of relevant cytokines, and induction of apoptosis in tumor cells. These results support the concept that tumor-reactive TGF-β-insensitive CD8+ T cells may prove beneficial in the treatment of advanced cancer patients.

Original languageEnglish (US)
Pages (from-to)235-247
Number of pages13
JournalProstate
Volume66
Issue number3
DOIs
StatePublished - Feb 15 2006

Fingerprint

Transforming Growth Factor beta
Apoptosis
T-Lymphocytes
Neoplasms
Adoptive Transfer
Cytokines
Neoplasm Metastasis
Immune Evasion
Lung
Immunosuppressive Agents
Inbred C57BL Mouse
Natural Killer Cells
Interleukin-2

Keywords

  • Adoptive transfer
  • CD8 T cell
  • Gene therapy
  • Immunosurveillance
  • TGF-β
  • Tumor rejection

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

Zhang, Qiang ; Jang, Thomas L. ; Yang, Ximing ; Park, Irwin ; Meyer, Robert E. ; Kundu, Shilajit ; Pins, Michael ; Javonovic, Borko ; Kuzel, Timothy ; Kim, Seong Jin ; Van Parijs, Luk ; Smith, Norm ; Wong, Larry ; Greenberg, Norman M. ; Guo, Yinglu ; Lee, Chung. / Infiltration of tumor-reactive transforming growth factor-beta insensitive CD8+ T cells into the tumor parenchyma is associated with apoptosis and rejection of tumor cells. In: Prostate. 2006 ; Vol. 66, No. 3. pp. 235-247.
@article{4b17d6f05e7d4b31b4dee8d0f158889e,
title = "Infiltration of tumor-reactive transforming growth factor-beta insensitive CD8+ T cells into the tumor parenchyma is associated with apoptosis and rejection of tumor cells",
abstract = "BACKGROUND. TGF-β is a potent immunosuppressant. High levels of TGF-β produced by cancer cells have a negative inhibition effect on surrounding host immune cells and leads to evasion of the host immune surveillance and tumor progression. In the present study, we report a distinct ability of tumor reactive, TGF-β-insensitive CD8+ T cells to infiltrate into established tumors, secrete relevant cytokines, and induce apoptosis of tumor cells. METHODS. CD8+ T cells were isolated from the spleens of C57BL/6 mice, which were primed with irradiated mouse prostate cancer cells, the TRAMP-C2 cells. After ex vivo expansion, these tumor reactive CD8+ cells were rendered TGF-β-insensitive by infection with a retroviral (MSCV)-mediated dominant negative TGF-β type II receptor (TβRIIDN). Control CD8+ cells consist of those transfected with the GFP-only empty vector and na{\"i}ve CD8+ T cells. Recipient mice were challenged with a single injection of TRAMP-C2 cells 21 days before adoptive transfer of CD8+ T cells was performed. Forty days after the adoptive transfer, all animals were sacrificed. The presence of pulmonary metastases was evaluated pathologically. Serial slides of malignant tissues were used for immunofluorescent staining for different kinds of immune cell infiltration, cytokines, and apoptosis analysis. RESULTS. Pulmonary metastases were either eliminated or significantly reduced in the group receiving adoptive transfer of tumor-reactive TGF-β-insensitive CD8+ T cells (3 out of 12) when compared to GFP controls (9 out of 12), and na{\"i}ve CD8 + T cells (12 out of 12). Results of immunofluorescent studies demonstrated that only tumor-reactive TGF-β-insensitive CD8+ T cells were able to infiltrate into the tumor and mediate apoptosis when compared to CD4+ T cells, NK cells, and B cells. A large amount of cytokines such as perform, nitric oxide, IFN-γ, IL-2, TNF-α were secreted in tumor tissue treated with tumor-reactive TGF-β-insensitive CD8+ T cells. No immune cells infiltration and cytokine secretion were detected in tumor tissues treated with na{\"i}ve T cells and GFP controls. CONCLUSIONS. Our results demonstrate the mechanism of anti-tumor effect of tumor-reactive TGF-β-insensitive CD8+ T cells that adoptive transfer of these CD8+ T cells resulted in infiltration of these immune cells into the tumor parenchyma, secretion of relevant cytokines, and induction of apoptosis in tumor cells. These results support the concept that tumor-reactive TGF-β-insensitive CD8+ T cells may prove beneficial in the treatment of advanced cancer patients.",
keywords = "Adoptive transfer, CD8 T cell, Gene therapy, Immunosurveillance, TGF-β, Tumor rejection",
author = "Qiang Zhang and Jang, {Thomas L.} and Ximing Yang and Irwin Park and Meyer, {Robert E.} and Shilajit Kundu and Michael Pins and Borko Javonovic and Timothy Kuzel and Kim, {Seong Jin} and {Van Parijs}, Luk and Norm Smith and Larry Wong and Greenberg, {Norman M.} and Yinglu Guo and Chung Lee",
year = "2006",
month = "2",
day = "15",
doi = "10.1002/pros.20340",
language = "English (US)",
volume = "66",
pages = "235--247",
journal = "Prostate",
issn = "0270-4137",
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Zhang, Q, Jang, TL, Yang, X, Park, I, Meyer, RE, Kundu, S, Pins, M, Javonovic, B, Kuzel, T, Kim, SJ, Van Parijs, L, Smith, N, Wong, L, Greenberg, NM, Guo, Y & Lee, C 2006, 'Infiltration of tumor-reactive transforming growth factor-beta insensitive CD8+ T cells into the tumor parenchyma is associated with apoptosis and rejection of tumor cells', Prostate, vol. 66, no. 3, pp. 235-247. https://doi.org/10.1002/pros.20340

Infiltration of tumor-reactive transforming growth factor-beta insensitive CD8+ T cells into the tumor parenchyma is associated with apoptosis and rejection of tumor cells. / Zhang, Qiang; Jang, Thomas L.; Yang, Ximing; Park, Irwin; Meyer, Robert E.; Kundu, Shilajit; Pins, Michael; Javonovic, Borko; Kuzel, Timothy; Kim, Seong Jin; Van Parijs, Luk; Smith, Norm; Wong, Larry; Greenberg, Norman M.; Guo, Yinglu; Lee, Chung.

In: Prostate, Vol. 66, No. 3, 15.02.2006, p. 235-247.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Infiltration of tumor-reactive transforming growth factor-beta insensitive CD8+ T cells into the tumor parenchyma is associated with apoptosis and rejection of tumor cells

AU - Zhang, Qiang

AU - Jang, Thomas L.

AU - Yang, Ximing

AU - Park, Irwin

AU - Meyer, Robert E.

AU - Kundu, Shilajit

AU - Pins, Michael

AU - Javonovic, Borko

AU - Kuzel, Timothy

AU - Kim, Seong Jin

AU - Van Parijs, Luk

AU - Smith, Norm

AU - Wong, Larry

AU - Greenberg, Norman M.

AU - Guo, Yinglu

AU - Lee, Chung

PY - 2006/2/15

Y1 - 2006/2/15

N2 - BACKGROUND. TGF-β is a potent immunosuppressant. High levels of TGF-β produced by cancer cells have a negative inhibition effect on surrounding host immune cells and leads to evasion of the host immune surveillance and tumor progression. In the present study, we report a distinct ability of tumor reactive, TGF-β-insensitive CD8+ T cells to infiltrate into established tumors, secrete relevant cytokines, and induce apoptosis of tumor cells. METHODS. CD8+ T cells were isolated from the spleens of C57BL/6 mice, which were primed with irradiated mouse prostate cancer cells, the TRAMP-C2 cells. After ex vivo expansion, these tumor reactive CD8+ cells were rendered TGF-β-insensitive by infection with a retroviral (MSCV)-mediated dominant negative TGF-β type II receptor (TβRIIDN). Control CD8+ cells consist of those transfected with the GFP-only empty vector and naïve CD8+ T cells. Recipient mice were challenged with a single injection of TRAMP-C2 cells 21 days before adoptive transfer of CD8+ T cells was performed. Forty days after the adoptive transfer, all animals were sacrificed. The presence of pulmonary metastases was evaluated pathologically. Serial slides of malignant tissues were used for immunofluorescent staining for different kinds of immune cell infiltration, cytokines, and apoptosis analysis. RESULTS. Pulmonary metastases were either eliminated or significantly reduced in the group receiving adoptive transfer of tumor-reactive TGF-β-insensitive CD8+ T cells (3 out of 12) when compared to GFP controls (9 out of 12), and naïve CD8 + T cells (12 out of 12). Results of immunofluorescent studies demonstrated that only tumor-reactive TGF-β-insensitive CD8+ T cells were able to infiltrate into the tumor and mediate apoptosis when compared to CD4+ T cells, NK cells, and B cells. A large amount of cytokines such as perform, nitric oxide, IFN-γ, IL-2, TNF-α were secreted in tumor tissue treated with tumor-reactive TGF-β-insensitive CD8+ T cells. No immune cells infiltration and cytokine secretion were detected in tumor tissues treated with naïve T cells and GFP controls. CONCLUSIONS. Our results demonstrate the mechanism of anti-tumor effect of tumor-reactive TGF-β-insensitive CD8+ T cells that adoptive transfer of these CD8+ T cells resulted in infiltration of these immune cells into the tumor parenchyma, secretion of relevant cytokines, and induction of apoptosis in tumor cells. These results support the concept that tumor-reactive TGF-β-insensitive CD8+ T cells may prove beneficial in the treatment of advanced cancer patients.

AB - BACKGROUND. TGF-β is a potent immunosuppressant. High levels of TGF-β produced by cancer cells have a negative inhibition effect on surrounding host immune cells and leads to evasion of the host immune surveillance and tumor progression. In the present study, we report a distinct ability of tumor reactive, TGF-β-insensitive CD8+ T cells to infiltrate into established tumors, secrete relevant cytokines, and induce apoptosis of tumor cells. METHODS. CD8+ T cells were isolated from the spleens of C57BL/6 mice, which were primed with irradiated mouse prostate cancer cells, the TRAMP-C2 cells. After ex vivo expansion, these tumor reactive CD8+ cells were rendered TGF-β-insensitive by infection with a retroviral (MSCV)-mediated dominant negative TGF-β type II receptor (TβRIIDN). Control CD8+ cells consist of those transfected with the GFP-only empty vector and naïve CD8+ T cells. Recipient mice were challenged with a single injection of TRAMP-C2 cells 21 days before adoptive transfer of CD8+ T cells was performed. Forty days after the adoptive transfer, all animals were sacrificed. The presence of pulmonary metastases was evaluated pathologically. Serial slides of malignant tissues were used for immunofluorescent staining for different kinds of immune cell infiltration, cytokines, and apoptosis analysis. RESULTS. Pulmonary metastases were either eliminated or significantly reduced in the group receiving adoptive transfer of tumor-reactive TGF-β-insensitive CD8+ T cells (3 out of 12) when compared to GFP controls (9 out of 12), and naïve CD8 + T cells (12 out of 12). Results of immunofluorescent studies demonstrated that only tumor-reactive TGF-β-insensitive CD8+ T cells were able to infiltrate into the tumor and mediate apoptosis when compared to CD4+ T cells, NK cells, and B cells. A large amount of cytokines such as perform, nitric oxide, IFN-γ, IL-2, TNF-α were secreted in tumor tissue treated with tumor-reactive TGF-β-insensitive CD8+ T cells. No immune cells infiltration and cytokine secretion were detected in tumor tissues treated with naïve T cells and GFP controls. CONCLUSIONS. Our results demonstrate the mechanism of anti-tumor effect of tumor-reactive TGF-β-insensitive CD8+ T cells that adoptive transfer of these CD8+ T cells resulted in infiltration of these immune cells into the tumor parenchyma, secretion of relevant cytokines, and induction of apoptosis in tumor cells. These results support the concept that tumor-reactive TGF-β-insensitive CD8+ T cells may prove beneficial in the treatment of advanced cancer patients.

KW - Adoptive transfer

KW - CD8 T cell

KW - Gene therapy

KW - Immunosurveillance

KW - TGF-β

KW - Tumor rejection

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U2 - 10.1002/pros.20340

DO - 10.1002/pros.20340

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