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Cell and Tumor Biology |
Departments of 1 Urology, 2 Pathology, 3 Preventive Medicine, and 4 Medicine, Northwestern University's Feinberg School of Medicine, Chicago, Illinois; 5 Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland; 6 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts; 7 Fred Hutchinson Cancer Research Center, Seattle, Washington; and 8 Institute of Urology, Peking University, Beijing, China
Requests for reprints: Chung Lee, Northwestern University's Feinberg School of Medicine, 303 East Chicago Avenue, Tarry 16-733, Chicago, IL 60611. Phone: 312-908-2004; Fax: 312-908-7572; E-mail: c-lee7{at}northwestern.edu.
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Key Words: TGF-ß • adoptive transfer • gene therapy • CD8+ T cell • immunosurveillance • tumor rejection
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Introduction |
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Historically, adoptive transfer of lymphokine-activated killer cells was first attempted, in which ex vivo culture of autologous lymphocytes with interleukin 2 (IL-2) to increase the number of activated effector cells. However, a clinical benefit was not shown by this approach (2). Subsequently, tumor-infiltrating lymphocytes were isolated from surgical specimens, clonally expanded by ex vivo culture with IL-2, and adoptively transferred to the patient (3). Although the initial results were promising, results of a phase III randomized trial using CD8+ tumor-infiltrating lymphocytes in combination with IL-2 failed to show an improved response in patients with metastatic renal cell carcinoma (4). Two recent studies represent the state-of-the-art strategies in adoptive therapy for cancer. In the first study (5), authors selected antigen-specific CD8+ T cells for ex vivo expansion and transfer into patients. Responses were remarkable but these CD8+ T cells did not persist, requiring repeated transfer of CD8+ T cells to elicit responses from the patients. In the second study (6), authors treated autologous tumor-infiltrating lymphocyte cells with IL-2 for ex vivo expansion and then transferred to patients following lymphodepletion. Although long-term engraftment was achieved, only 4 of 35 patients showed complete response. These results, although impressive, fall short of our expectation (i.e., total elimination of tumor cells in most patients).
In considering tumor immunotherapy, the issue of tumor-derived immune suppression must be taken into consideration (1). It seems that despite the ability to generate immune cells reactive against cancer antigens, tumor escape mechanisms can overpower these immune reactions with an eventual tumor progression (7). Tumor cells have acquired many mechanisms to evade the host immune surveillance (8, 9). One of such possibilities has been the down-regulation of tumor antigen processing (10). Tumor-specific CD4+CD25+ T regulatory cells can also inhibit CD8+ T-cell function (11). Tumor-derived immunosuppressive cytokines, including vascular endothelial growth factor, IL-10, and transforming growth factor (TGF)-ß (9, 12–14), also contribute to tumor evasion of the host immune surveillance. In the present study, we propose to focus on TGF-ß-mediated evasion of immune surveillance.
Tumor cells secrete large amounts of TGF-ß. High levels of TGF-ß produced by cancer cells have a negative impact on surrounding cells, including the host immune cells (15). TGF-ß is a potent tumor-induced immunosuppressant (8, 12, 16–20). Therefore, TGF-ß seems to be an attractive target for anticancer therapy. The first piece of work describing immune-mediated eradication of tumors through the blockade of TGF-ß signaling in T cells was reported by Gorelik and Flavell (17). These authors used transgenic mice with TGF-ß null expression targeted specifically to T cells. Subsequently, our study using transplant of TGF-ß-insensitive bone marrow cells also showed a total rejection of metastatic tumor cells (19, 20). However, in both studies, due to the nonspecific nature of the immune cells, autoimmune disease eventually developed in the hosts.
In the present study, we attempted to combine the above two advanced technologies by employing adoptive transfer of tumor-reactive TGF-ß-insensitive CD8+ T cells into tumor-bearing mice. Here, we report that these CD8+ T cells showed a robust antitumor activity with little or no apparent toxicity.
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Materials and Methods |
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Generation of Tumor-Reactive CD8+ T Cells. Mice were primed with irradiated TRAMP-C2 cells (5 x 106 per mice at 20,000 Ci) by s.c. injection every 10 days for a total of three inoculations. Two weeks following the last vaccination, splenic CD8+ T cells were isolated by using murine T cell CD8+subset column kit (R&D Systems, Minneapolis, MN) and were expanded (105/mL) in the presence of TRAMP-C2 lysates (1 x 106) and irradiated autologous splenocytes (1 x 106/mL at 3,000 Ci) in medium containing RPMI 1640 with 10% fetal bovine serum, IL-2 (50 units/mL), anti-CD3+ monoclonal antibody (30 ng/mL, R&D Systems), HEPE (25 mmol/L), L-glutamine (4 mmol/L), and 2-ME (25 mmol/L). Media were changed every 3 days.
Infection with Retrovirus Containing Dominant Negative TGF-ß Type II Receptor or Green Fluorescent Protein. CD8+ T cells were cultured for at least 10 weeks before they were infected with the murine stem cell virus retrovirus containing the dominant-negative TGF-ß type II receptor (TßRIIDN) and green fluorescent protein (GFP; Fig. 2A; refs. 19, 20). The infection efficiency was 93.9% for the TßRIIDN vector and 92.8% for the GFP control vector (Fig. 2B). There were three types of CD8+ T cells. The first type was tumor-reactive TGF-ß-insensitive CD8+ T cells (tumor-reactive CD8+ T cells infected with the virus containing TßRIIDN). The second type was tumor-reactive CD8+ T cells infected with the virus containing the GFP control vector. The third type was naive CD8+ T cells, which were freshly isolated from the spleen of naive donor animals without any treatment.
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In vivo Antitumor Assay. Mice received a single injection of 5 x 105 TRAMP-C2 cells via the tail vein. Adoptive transfer of CD8+ T cells (2 x 106) was done on either day 3, 7, or 21 following tumor cell injection. Mice were maintained on antibiotics (sulfamethoxazole-trimethoprim) for a minimum of 2 weeks to prevent opportunistic infection after the injection. Forty days after the adoptive transfer, all animals were sacrificed. Some animals were sacrificed sooner than 40 days due to poor health conditions. Serum levels of IFN-
and IL-2 were determined by ELISA. Splenic CD8+ T cells were isolated, and the percentage of GFP-positive CD8+ T cells in each spleen was calculated following analysis by flow cytometry.
Histologic Procedures. For each animal, upon euthanasia, the lung was excised, fixed in formalin, embedded in paraffin, and serially sectioned at 4-nm thickness until the block was exhausted. Routine H&E staining was done at an interval of every 10 sections. The unstained paraffin sections were used for studies described below.
Nuclear Staining, Apoptosis Assay, and CD8+ Staining. Tissue sections were subjected to apoptosis assay by using the TUNEL apoptosis kit (Upstate, Lake Placid, NY) and were labeled with Avidin-FITC (green, 50 µL). The same slides were treated with blocking buffer and probed for CD8 with rat monoclonal antibody, which was labeled with APC (red; 2 µg/mL, Santa Cruz Biotechnology, Santa Cruz, CA). Finally, the same slides were stained for cell nuclei with VECTASHIELD mounting media (blue; Vector Laboratories, Burlingame, CA). They were viewed with Nikon TE2000-U fluorescent microscopy (Nikon Co., Tokyo, Japan). Images were digitized by Photoshop 7.0 software.
Expression of TGF-ß Receptors in CD8+ T Cells. Normal CD8+ T cells, isolated from freshly harvested spleens, were subjected to fixation and permeabilization in preparation for immunofluorescent staining and flow cytometry analysis. Cells were stained with phycoerytherin-conjugated monoclonal antibody against TGF-ß type I receptor (1:100 dilution; Santa Cruz Biotechnology), and TGF-ß type II receptor (1:50 dilution, Santa Cruz Biotechnology). They were then stained with FITC-conjugated monoclonal antibody against CD8 (Santa Cruz Biotechnology). These cells were subjected to dual analysis for phycoerytherin and FITC by flow cytometry.
Western Blot Analysis for SMAD-2 Phosphorylation. CD8+ T cells were treated with or without 10 ng/mL of TGF-ß1 for 16 hours (19). Cell lysates were prepared by adding radioimmunoprecipitation assay buffer (50 mmol/L Tris-HCl, 1% NP40, 0.25% Na-deoxycholate, 150 mmol/L NaCl, 1 mmol/L EDTA, 1 mmol/L Na3VO4, and 1 mmol/L NaF) to cell pellets. Approximately 30 µg of total protein extract were loaded onto 10% acrylamide gel in Tris-HCl (Bio-Rad, Hercules, CA). Electrophoresis was carried out in Tris-glycine-SDS running buffer and transferred to a polyvinylidene difluoride membrane. Blots were probed for phosphorylated SMAD-2 with a monoclonal antibody. They were then stripped and reprobed for SMAD-2 and glyceraldehyde-3-phosphate dehydrogenase. Proteins of interest were detected with the enhanced chemiluminescence detection kit (Amersham Biosciences, Buckinghamshire, United Kingdom) followed by exposure to Kodak X-OMAT AR film.
Plasminogen Activator Inhibitor-1 Promoter-Reporter Activity Assay. CD8+ T cells were transiently transfected with a promoter construct, 3TP-Lux, which contains multiple copies of TGF-ß response element, using LipofectAMINE 2000 (Invitrogen, Carlsbad, CA). Cells were treated with 10 ng/mL of TGF-ß1 for 16 hours. Luciferase activity was assayed by using an assay kit (Promega, San Diego, CA). Activity was normalized based on ß-galactosidase expression with pSVß-galactosidase.
Thymidine Incorporation Assay. CD8+ T cells (3 x 104 cells per 24 wells) were treated with or without TGF-ß1 (10 ng/mL) for 16 hours. A medium containing [3H]-thymidine (0.5 µCi/mL; Amersham Biosciences) was introduced and cells were cultured for additional 5 hours. The experiment was terminated by washing with warm serum-free medium. NaOH (0.1 mol/L) was added to all wells (1 mL). An aliquot of 100 µL was removed for measurement of the protein content and the remainder was used for determining the radioactivity. Thymidine incorporation was expressed as the fraction of counts found in controls.
TGF-ß1 ELISA Assay. TRAMP-C2 cells (1.0 x 107 per T75 flask) were cultured in serum-free media for 24 hours. The medium was replaced for 24 hours. The pooled conditioned medium was collected and concentrated by using YM-3 Centriprep Centrifugal Filter Devices (Millipore Co., Bedford, MA). After activation of TGF-ß1 by treatment with 1 N HCl (0.1 mL per 0.5mL per conditioned media), the mixture was neutralized by 0.1 mL 1.2 N NaOH/0.5 mol/L HEPES. The ELISA assay was carried out using the Quantikine Human TGF-ß1 Immunoassay Kit from R&D Systems (Minneapolis, MN). The total number of cells in each flask was counted using a Coulter Counter and levels of TGF-ß1 were reported as pg per 105 cells per 48 hours.
Fate of Tumor-Reactive CD8+ T Cells in the Spleen. Because tumor-reactive CD8+ T cells are labeled with GFP, the percent of GFP positive CD8+ T cells in the spleen was determined by flow cytometry. This experiment was carried out in both tumor-free animals and in tumor-bearing animals at different time points.
Statistical Methods. All in vitro experiments were done in triplicate. Numerical data were expressed as mean ± SD. ANOVA and multiple range test were done to determine differences of means among different treatment groups. P < 0.05 was considered statistically significant. The SPSS 10.0.7 software package (SPSS, Inc., Chicago, IL) was used for analysis. Kaplan-Meier survival curve was analyzed by the log-rank test using the Graphpad Prism 4.02 software (Graphpad Software, Inc., San Diego, CA).
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Results |
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In vitro Antitumor Activity of Tumor-Reactive TGF-ß-Insensitive CD8+ T Cells. Tumor-reactive TGF-ß-insensitive CD8+ T cells showed a potent-specific lysis against TRAMP-C2 cells (Fig. 3A). These cells showed a 5-fold more tumor-killing activity than that of TGF-ß-sensitive counterpart and 25-fold over that of naive CD8+ T cells. Both the TGF-ß-sensitive and TGF-ß-insensitive tumor-reactive CD8+ T cells showed a reduced tumor-killing activity when incubated with an irrelevant cell line, mouse B16-F10 melanoma cells (Fig. 3B).
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Fate of Transferred CD8+ T Cells. In the present study, a total of 2 x 106 CD8+ T cells were transferred into each recipient animal. This number was derived by extrapolating the comparable number of T cells in adoptive therapy for cancer patients (1, 6) . In a similar study with adoptive transfer of experimental melanoma model, 3 x 106 antigen-specific T cells were used (21). To determine the fate of these transferred cells, we measured the percentage of GFP-positive CD8+ T cells in the spleen of recipient animals. When CD8+ T cells were adoptively transferred to tumor-free hosts, there was a linear decay in GFP-positive CD8+ T cells reaching 0% by 30 days for tumor-reactive CD8+ T cells infected with the GFP control vector and 50 days for tumor-reactive CD8+ T cells infected with the TßRIIDN vector (Fig. 6B). However, when tumor-reactive TGF-ß-insensitive CD8+ T cells were adoptively transferred to tumor-bearing hosts (the TßRIIDN group), the percentage of GFP-positive CD8+ T cells was maintained at 2% for at least 40 days; whereas in animals which received adoptive transfer of tumor-reactive control CD8+ T cells (the GFP group), GFP-positive CD8+ T cells showed a decay curve similar to that in tumor-free hosts with a slight delay (Fig. 6C).
Serum Levels of IFN- and IL-2. In animals which received adoptive transfer of naive CD8+ T cells, there was a baseline level of IL-2 and IFN-. In animals which received tumor-reactive control CD8+ T cells (the GFP group), there was a significant increase in both cytokines. A further increase in serum IL-2 (Fig. 6D) and IFN- (Fig. 6E) was observed when these cells were rendered insensitive to TGF-ß (the TßRIIDN group), suggesting the presence of activated immune cells in these hosts.
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Discussion |
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A significant part of tumor immunology has focused on the identification of tumor-specific antigens and the cytolytic T cells specific for these peptides (22). Adoptive T-cell therapy using antigen-specific CD8+ T cells for cancer treatment has been attempted with some degree of success (5, 23) and seems to be an advantage over the transfer of nonspecific T cells (21). Results of the present study have shown that adoptive transfer of tumor-reactive and TGF-ß-insensitive CD8+ T cells were able to specifically target against autologous tumor cells and eradicate established pulmonary metastasis. The use of tumor-specific adoptive immunotherapy has reported before and has clearly shown its efficacy by other investigators (23, 24). The critical issue in immunotherapy thus far has been the tumor-derived immunosuppressive effect, which remains unresolved.
The mouse prostate cancer model, TRAMP-C2, represents an aggressive line of malignant cells, which secrete large amounts of TGF-ß. The role of immunosuppressive effect of TGF-ß in cancer progression has been well established (13, 25–27). In the present study, we have shown that, TRAMP-C2 tumors possess potent immunosuppressive power so that regular CD8+ T cells are unable to infiltrate into the tumor tissues. However, if these tumor-reactive CD8+ T cells are engineered and rendered insensitive to TGF-ß, they are able to infiltrate into the tumor tissue and induce apoptosis in these established TRAMP-C2 tumors. To the best of our knowledge, studies to test this concept have not been attempted before. These results support the concept that TGF-ß is an important target in cancer therapy.
Results of the present study show that in tumor-bearing hosts, the transferred CD8+ T cells persist, only if they are tumor reactive and TGF-ß insensitive. Therefore, adoptive transfer of tumor-reactive TGF-ß-insensitive CD8+ T cells will persist in tumor-bearing hosts and does not require the procedure of lymphodepletion. Interestingly, these cells decayed in tumor-free hosts. Accompanied with the persistence of these transferred CD8+ T cells were elevated circulating levels of IL-2 and IFN-, a critical requirement for antitumor activity in the host (24). Therefore, with our current approach of adoptive transfer of tumor-reactive TGF-ß-insensitive CD8+ T cells, exogenous treatment of IL-2 is not necessary for a successful antitumor activity. On the other hand, naive CD8+ T cells and tumor-reactive CD8+ T cells but sensitive to TGF-ß did not persist in the host, suggesting that these cells failed to establish an engraftment regardless the status of the presence or absence of tumor cells in the host. These observations suggest that a single transfer of tumor-reactive TGF-ß-insensitive CD8+ T cells is sufficient for tumor rejection.
Our results also indicate that CD8+ T cells contain high levels of TGF-ß receptor types I and II and therefore, are highly sensitive to the inhibitory effects of TGF-ß. The role of TGF-ß in the immune system is best shown in TGF-ß knockout animals. Mice lacking TGF-ß, although they grew normally for the first 2 weeks, develop rapid wasting syndrome, and die by 3 to 4 weeks of age (28, 29). These studies showed a powerful immunoregulatory role of TGF-ß because TGF-ß–/– mice had excessive inflammatory responses with massive infiltration of lymphocytes and macrophages in multiple organs. These syndromes were characterized as autoimmunity (17, 29). Results of our past study have shown that mice receiving TGF-ß-insensitive bone marrow transplants have met with the same fate by developing autoimmune syndrome, although these animals were able to eliminate challenged tumors (19, 20) . In the present study, the use of the tumor-specific TGF-ß-insensitive CD8+ T cells for the treatment of established cancer did not result in the development of massive infiltration of immune cells into the airspace of the lung of tumor-bearing host and, in tumor-free hosts, these CD8+ T cells failed to persist in the host. These preliminary observations seem to suggest an apparent absence of the development of autoimmune disease in these animals. Further studies are warranted to verify this impression.
In summary, the present results showed that adoptive transfer of tumor-reactive TGF-ß-insensitive CD8+ T cells to tumor-bearing hosts was able to eradicate autologous tumors. These CD8+ T cells have the following characteristic properties. First, they are specifically reactive against tumor tissues. Second, they are insensitive to TGF-ß. These two properties endowed these CD8+ T cells with the ability to infiltrate into tumor tissues and function as potent effectors against tumor cells. Finally, these cells are able to persist in tumor-bearing hosts but not in tumor-free hosts. These findings provide a proof of principle that an adoptive transfer of tumor-reactive TGF-ß-insensitive CD8+ T cells may warrant consideration for the treatment of advanced cancers.
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Acknowledgments |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 9/ 2/04. Revised 11/11/04. Accepted 12/14/04.
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2 test, indicated that values in the TßRIIDN group are significantly different from those of other two groups (P < 0.001). Also, values in the GFP group are significantly different from those of the naive group (P < 0.001). C, Kaplan-Meier survival curve of tumor-bearing mice received adoptive transfer of naive CD8+ T cells (dotted line with solid circles), GFP control vector (solid line with solid circles), and TßRIIDN-transfected CD8+ T cells (dotted line with open circles). P < 0.05 according to the log-rank test for the TßRIIDN group versus the naive or GFP group.
