Adoptive Transfer of Tumor-Reactive Transforming Growth Factor-β–Insensitive CD8+ T Cells: Eradication of Autologous Mouse Prostate Cancer

Abstract

Transforming growth factor (TGF)-B is a potent immunosuppressant. Overproduction of TGF-B 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-B-insensitive CD8 + + T cells. The mouse TRAMP-C2 prostate cancer cells produced large amounts of TGF-B1 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-B insensitive by infecting with a retrovirus containing dominant-negative TGF-B 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-B-insensitive CD8 + + T cells. Results of immunofluorescent studies showed that only tumor-reactive TGF-B-insensitive CD8 + + T cells were able to infiltrate into the tumor and mediate apoptosis in tumor cells. Furthermore, transferred tumor-reactive TGF-B-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-B-insensitive CD8 + + T cells may warrant consideration for cancer therapy.

Systemic Oncolytic Herpes Virus Therapy of Poorly Immunogenic Prostate Cancer Metastatic to Lung

“…Reasons for the lack of in vitro CTL activity are unclear but could include: (a) no TRAMP-C2 -specific CTLs were generated in this model system. A recent study reported that TRAMP-C2 cells secrete large amounts of the potent immunosuppressant transforming growth factor-h, which could prevent CD8 + cells from infiltrating into metastatic lung tumors (36). Based on this report, we did in vitro stimulation of splenocytes with TRAMP-C2 cells in the presence of antitransforming growth factor-h antibodies; however, the CTL assay was again unsuccessful.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…Indeed, tumors have been shown to escape the anti-tumor immune responses by generating an immunosuppressed tumor microenvironment. Tumors often produce soluble immunosuppressive factors, such as TGFβ [13,68,69], VEGF [69,70], IL-10 [69,71], iNOS [72,73], PGE 2 [74,75], and gangliosides [76,77], that act on neutrophils and other tumor infiltrating immune cells. Often, progressive immunosuppression is observed at advanced tumor stages, which is partially mediated by tumor-infiltrating immunosuppressive immune cells such as regulatory T (Treg) cells, Th17 cells, regulatory dendritic cells, TAMs, TANs and MDSCs.…”

“…These ex vivo expanded TGFβ-insensitive CD8 + T cells infiltrated the tumor and mediated apoptosis in tumor cells [68]. Fridlender et al [13] showed that inhibition of TGFβ signaling using the small molecule inhibitor SM16 conferred anti-tumorigenic activity to neutrophils.…”

Targeting tumors with LIGHT to generate metastasis-clearing immunity

“…While active TGF-β does not inhibit lysis by CTLs, it can inhibit maturation of T cells to that effector state [79]. This explains, at least in part, how CD8 + T cells resistant to TGF-β1 can mediate tumor rejection [80].…”