Adoptive transfer of tumor-reactive transforming growth factor-beta-insensitive CD8+ T cells: eradication of autologous mouse prostate cancer.

Transforming growth factor (TGF)-beta is a potent immunosuppressant. Overproduction of TGF-beta by tumor cells may lead to tumor evasion from the host immune surveillance and tumor progression. The present study was conducted to develop a treatment strategy through adoptive transfer of tumor-reactive TGF-beta-insensitive CD8+ T cells. The mouse TRAMP-C2 prostate cancer cells produced large amounts of TGF-beta1 and were used as an experimental model. C57BL/6 mice were primed with irradiated TRAMP-C2 cells. CD8+ T cells were isolated from the spleen of primed animals, were expanded ex vivo, and were rendered TGF-beta insensitive by infecting with a retrovirus containing dominant-negative TGF-beta type II receptor. Results of in vitro cytotoxic assay revealed that these CD8+ T cells showed a specific and robust tumor-killing activity against TRAMP-C2 cells but were ineffective against an irrelevant tumor line, B16-F10. To determine the in vivo antitumor activity, recipient mice were challenged with a single injection of TRAMP-C2 cells for a period up to 21 days before adoptive transfer of CD8+ T cells was done. Pulmonary metastasis was either eliminated or significantly reduced in the group receiving adoptive transfer of tumor-reactive TGF-beta-insensitive CD8+ T cells. Results of immunofluorescent studies showed that only tumor-reactive TGF-beta-insensitive CD8+ T cells were able to infiltrate into the tumor and mediate apoptosis in tumor cells. Furthermore, transferred tumor-reactive TGF-beta-insensitive CD8+ T cells were able to persist in tumor-bearing hosts but declined in tumor-free animals. These results suggest that adoptive transfer of tumor-reactive TGF-beta-insensitive CD8+ T cells may warrant consideration for cancer therapy.

[1]  S. Rosenberg,et al.  Cancer regression in patients with metastatic melanoma after the transfer of autologous antitumor lymphocytes , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[2]  S. Rosenberg,et al.  Bedside to bench and back again: how animal models are guiding the development of new immunotherapies for cancer , 2004, Journal of leukocyte biology.

[3]  S. Rosenberg.  Development of effective immunotherapy for the treatment of patients with cancer. , 2004, Journal of the American College of Surgeons.

[4]  L. Khawli,et al.  Complete regression of experimental solid tumors by combination LEC/chTNT-3 immunotherapy and CD25(+) T-cell depletion. , 2003, Cancer research.

[5]  Steven A. Rosenberg,et al.  Adoptive-cell-transfer therapy for the treatment of patients with cancer , 2003, Nature Reviews Cancer.

[6]  Y. Gong,et al.  Tumor-Derived TGF-β Reduces the Efficacy of Dendritic Cell/Tumor Fusion Vaccine1 , 2003, The Journal of Immunology.

[7]  Seong-Jin Kim,et al.  Suppression of tumor metastasis by blockade of transforming growth factor beta signaling in bone marrow cells through a retroviral-mediated gene therapy in mice. , 2002, Cancer research.

[8]  P. Greenberg,et al.  Adoptive therapy with CD8(+) T cells: it may get by with a little help from its friends. , 2002, The Journal of clinical investigation.

[9]  J. Thompson,et al.  Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: In vivo persistence, migration, and antitumor effect of transferred T cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[10]  N. Restifo,et al.  Natural selection of tumor variants in the generation of “tumor escape” phenotypes , 2002, Nature Immunology.

[11]  Seong-Jin Kim,et al.  Reconstitution of Lethally Irradiated Adult Mice with Dominant Negative TGF-β Type II Receptor-Transduced Bone Marrow Leads to Myeloid Expansion and Inflammatory Disease1 , 2002, The Journal of Immunology.

[12]  P. Greenberg,et al.  Adoptive therapy with CD8 + T cells , 2002 .

[13]  R. Flavell,et al.  Immune-mediated eradication of tumors through the blockade of transforming growth factor-β signaling in T cells , 2001, Nature Medicine.

[14]  W. Karpus,et al.  Down-regulation of TGF- β 1 production restores immunogenicity in prostate cancer cells , 2000, British Journal of Cancer.

[15]  James F. Jones,et al.  Elevated Serum Transforming Growth Factor β1 Levels in Epstein-Barr Virus-Associated Diseases and Their Correlation with Virus-Specific Immunoglobulin A (IgA) and IgM , 2000, Journal of Virology.

[16]  N. Fortunel,et al.  Transforming growth factor-b : pleiotropic role in the regulation of hematopoiesis , 2000 .

[17]  R. Figlin,et al.  Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  WM Kast,et al.  Effects of TGF-β on the immune system: implications for cancer immunotherapy , 1999, Leukemia.

[19]  H. Friess,et al.  Transforming growth factor betas and their signaling receptors in human hepatocellular carcinoma. , 1999, American journal of surgery.

[20]  S. Rosenberg,et al.  High avidity CTLs for two self-antigens demonstrate superior in vitro and in vivo antitumor efficacy. , 1999, Journal of immunology.

[21]  Anita B. Roberts,et al.  REGULATION OF IMMUNE RESPONSES BY TGF-β* , 1998 .

[22]  P. Bruggen,et al.  T cell defined tumor antigens , 1997 .

[23]  S. Wojtowicz-Praga.  Reversal of Tumor-Induced Immunosuppression: A New Approach to Cancer Therapy , 1997, Journal of immunotherapy.

[24]  Thomas C Chen,et al.  TGF-B2 and soluble p55 TNFR modulate VCAM-1 expression in glioma cells and brain derived endothelial cells , 1997, Journal of Neuroimmunology.

[25]  A. Kulkarni,et al.  Autoimmune manifestations in the transforming growth factor-beta 1 knockout mouse. , 1996, Blood.

[26]  R. Figlin,et al.  In vivo trafficking of adoptively transferred interleukin-2 expanded tumor-infiltrating lymphocytes and peripheral blood lymphocytes. Results of a double gene marking trial. , 1996, The Journal of clinical investigation.

[27]  J. Yewdell,et al.  Identification of human cancers deficient in antigen processing , 1993, The Journal of experimental medicine.

[28]  M. Sporn,et al.  Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[29]  H. Koeppen,et al.  A highly immunogenic tumor transfected with a murine transforming growth factor type beta 1 cDNA escapes immune surveillance. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[30]  A. Chang,et al.  A new approach to the therapy of cancer based on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2. , 1986, Surgery.