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1.
Bouet-Toussaint F Cabillic F Toutirais O Le Gallo M Thomas de la Pintière C Daniel P Genetet N Meunier B Dupont-Bierre E Boudjema K Catros V 《Cancer immunology, immunotherapy : CII》2008,57(4):531-539
Introduction Vγ9Vδ2 T lymphocytes are reported to participate in the anti-tumor immune surveillance in human. They are known to recognize
phosphoantigens and molecules expressed on cells undergoing neoplasic transformation. In this study, we investigated phenotype
and anti-tumor cytotoxicity of ex vivo expanded Vγ9Vδ2 T cells in view of adoptive immunotherapy.
Materials and Methods Experiments were performed with peripheral blood samples from eleven patients [six colorectal carcinoma (CRC), four hepatocellular
carcinoma (HCC), one sarcoma] and sixteen healthy donors.
Results/Discussion Ex vivo expansion of Vγ9Vδ2 T cells could be achieved by a single dose of phosphoantigen, either bromohydrin pyrophosphate
or zoledronate, and supported by exogenous IL-2. After 2 weeks, expanded Vγ9Vδ2 T lymphocytes acquired the effector memory
phenotype CD45RA−CD45ROhighCD27−. They expressed NKG2D and CD161 and the proinflammatory CXCR3 and CCR5 chemokine receptors. Vγ9Vδ2 T cells displayed a strong
lytic activity toward a broad panel of tumor cell lines or primary cultures. Interestingly, HCC and CRC primary cells could
be lysed by autologous Vγ9Vδ2 T cells whereas autologous normal cells were not sensitive to the lysis. mAbs blocking assays
demonstrated that TCR was the most important receptor involved in the lysis of tumor cells. However, NKG2D receptor could
deliver a costimulatory signal enhancing the lysis of HCC and CRC tumors expressing MICA/B. Treatment of tumor cells by the
mevalonate pathway inhibitor, zoledronate, enhanced the killing of both HCC and CRC. Expansion index of Vγ9Vδ2 T cells was
in similar levels in healthy donors or in cancer patients and total expansion was suitable for adoptive immunotherapy.
Conclusion These results provide a rationale for the clinical evaluation of Vγ9Vδ2 T lymphocytes in HCC and CRC. 相似文献
2.
Kobayashi H Tanaka Y Yagi J Minato N Tanabe K 《Cancer immunology, immunotherapy : CII》2011,60(8):1075-1084
Human Vγ2 Vδ2-bearing T cells have recently received much attention in cancer immunotherapy. In this study, we conducted a
phase I/II clinical trial of the adoptive transfer of γδ T cells to patients with advanced renal cell carcinoma. Eleven patients
who had undergone nephrectomy and had lung metastasis were enrolled. Peripheral blood γδ T cells obtained from the patients
were stimulated ex vivo with 2-methyl-3-butenyl-1-pyrophosphate (2M3B1PP), a synthetic pyrophosphomonoester antigen, and transferred
in combination with zoledronic acid (Zol) and teceleukin (recombinant human interleukin-2). Expanded γδ T cells exhibited
potent cytotoxic activity against tumor cells in vitro, and the proportion of peripheral blood γδ T cells among CD3+ cells typically peaked three to 5 days after transfer. Tumor doubling time was prolonged in all 11 patients, and the best
overall responses were 1 CR, 5 SD, and 5 PD, as defined based on Response Evaluation Criteria in Solid Tumors (RECIST). Although
ten patients developed adverse reactions of grade ≥3, they were likely to have been the result of the concomitant infusion
of Zol and IL-2, and most symptoms swiftly reverted to normal during the course of treatment. In conclusion, this clinical
trial demonstrated that our regimen for the adoptive transfer of γδ T cells in combination with Zol and IL-2 was well tolerated
and that objective clinical responses could be achieved in some patients with advanced renal cell carcinoma. 相似文献
3.
γδ T cells lyse autologous and allogenic oesophageal tumours: involvement of heat-shock proteins in the tumour cell lysis 总被引:4,自引:0,他引:4
Thomas ML Samant UC Deshpande RK Chiplunkar SV 《Cancer immunology, immunotherapy : CII》2000,48(11):653-659
T cells expressing γδ receptors were isolated from the peripheral blood of oesophageal cancer patients and analysed for their
potential to lyse tumour targets. Immunophenotyping by flow cytometry showed that the dominant population of γδ T cells expressed
the Vγ9 and the Vδ2 T cell receptor, and a minor population expressed the Vδ1 receptor. Cytotoxicity assays revealed that
activated γδ T cells lysed Daudi Burkitt's lymphoma and K562 cells. Lysis of autologous oesophageal tumours was higher than
of allogenic tumours. Anti-hsp60 and anti-hsp70 mAb significantly inhibited the cytotoxicity of γδ T cells to both autologous
and allogenic oesophageal tumours. Surface expression of hsp60 and hsp70 on oesophageal tumours and Daudi cells was demonstrated
by flow cytometry. In conclusion, γδ T cells isolated from the peripheral blood of oesophageal cancer patients have the ability
of kill oesophageal tumour cells. The lysis of tumour targets by the γδ T cells is brought about via recognition of heat-shock
proteins expressed on the surface of tumour cells. γδ T cells isolated from the peripheral blood may have applications in
adoptive immunotherapy of oesophageal cancer.
Received: 15 April 1999 / Accepted: 16 September 1999 相似文献
4.
5.
Jun Zhou Desheng Weng Fangjian Zhou Ke Pan Haifeng Song Qijing Wang Huan Wang Hui Wang Yongqiang Li Lixi Huang Huakun Zhang Wei Huang Jianchuan Xia 《Cancer immunology, immunotherapy : CII》2009,58(10):1587-1597
Renal cell carcinoma (RCC) has been shown to be susceptible to immunotherapeutic treatment strategies. In the present study,
patient-derived tumor cells were fused with allogeneic dendritic cells (DC) to elicit anti-tumor activity against RCC. DC
from HLA-A2+ healthy donors were fused with primary RCC cells from ten patients. Phenotype of fusion cells were characterized
by flow cytometer and confocal microscopy. In vitro, T cell proliferation, IFN-γ secretion and cytotocic T lymphocytes (CTL)
activity elicited by allogeneic DC/RCC fusion cells were assessed. Clinically, ten patients were vaccinated with allogeneic
DC/RCC fusion vaccine. The adverse effects and toxicity were observed. The clinical response was evaluated by CT scans. After
fusion, the created hybrids expressed both tumor associated antigen and DC-derived molecules and could stimulate the proliferation
and IFN-γ secretion of T cells as well as elicit strong CTL activity against RCC cells in vitro. In vivo, no serious adverse
effects, toxicity, or signs of autoimmune disease were observed after vaccination therapy. Percentage of T lymphocyte subsets
in peripheral blood of patients was increased significantly. One of ten patients exhibited a partial response with regression
of lung metastases. Six patients showed stable disease with stabilization of previously progressive disease (follow up 1.5 years).
The PR and SD responses, exhibited by 7/10 patients who received the allogeneic DC/RCC fusion vaccine treatment, suggest that
this approach is safe and can elicit immunological responses in a significant portion of patients with RCC.
J. Zhou and D. Weng contributed equally. 相似文献
6.
Altvater B Pscherer S Landmeier S Kailayangiri S Savoldo B Juergens H Rossig C 《Cancer immunology, immunotherapy : CII》2012,61(3):385-396
Specific cellular immunotherapy of cancer requires efficient generation and expansion of cytotoxic T lymphocytes (CTLs) that
recognize tumor-associated self-antigens. Here, we investigated the capacity of human γδ T cells to induce expansion of CD8+
T cells specific for peptides derived from the weakly immunogenic tumor-associated self-antigens PRAME and STEAP1. Coincubation
of aminobisphosphonate-stimulated human peripheral blood-derived γδ T cells (Vγ9+Vδ2+), loaded with HLA-A*02-restricted epitopes
of PRAME, with autologous peripheral blood CD8+ T cells stimulated the expansion of peptide-specific cytolytic effector memory
T cells. Moreover, peptide-loaded γδ T cells efficiently primed antigen-naive CD45RA+ CD8+ T cells against PRAME peptides.
Direct comparisons with mature DCs revealed equal potency of γδ T cells and DCs in inducing primary T-cell responses and peptide-specific
T-cell activation and expansion. Antigen presentation by γδ T-APCs was not able to overcome the limited capacity of peptide-specific
T cells to interact with targets expressing full-length antigen. Importantly, T cells with regulatory phenotype (CD4+CD25hiFoxP3+)
were lower in cocultures with γδ T cells compared to DCs. In summary, bisphosphonate-activated γδ T cells permit generation
of CTLs specific for weakly immunogenic tumor-associated epitopes. Exploiting this strategy for effective immunotherapy of
cancer requires strategies that enhance the avidity of CTL responses to allow for efficient targeting of cancer. 相似文献
7.
Tomohiro Yamaguchi Youichi Suzuki Ryuichi Katakura Takusaburo Ebina Junkichi Yokoyama Yoshiaki Fujimiya 《Cancer immunology, immunotherapy : CII》1998,47(2):97-103
γδT cells play a regulatory role in both primary and metastatic tumor growth in humans. The mechanisms responsible for the
activation and proliferation of circulating γδT cells should be fully understood prior to their adoptive transfer to cancer
patients. We have examined in vitro functional effects of interleukin-15 (IL-15) on highly purified γδT cells isolated from
glioblastoma patients. γδT cells constitutively express the heterotrimeric IL-2 receptor (IL-2R) αβγ, but the levels of IL-2Rβ
or γ expression were not increased by incubation with saturating amounts of IL-15. IL-15 was shown to induce a maximal γδT
cell proliferation, although at much higher concentrations (at least 2000 U/ml) than IL-2 (100 U/ml). Submaximal concentrations
of IL-15 plus low concentrations of IL-2 produced an additive proliferative response. In contrast to the IL-2-induced response,
this activity was completely or partially abrogated by anti-IL-2Rβ, or anti-IL-2Rγ antibodies, but not by anti-IL-2Rα antibodies.
Incubation of γδT cells in the presence of IL-15 resulted not only in the appearance of NK and LAK activity, but also in specific
autologous tumor cell killing activity, an additive effect being seen with IL-15 and IL-2. This IL-15-induced tumor-specific
activity could be significantly blocked by anti-IL-2Rγ and anti-IL-2R-β mAb, but not by anti-IL-2Rα mAb. Thus, in contrast
to IL-2, IL-15 activates tumor-specific γδT cells through the components of IL-2Rβ and IL-2Rγ, but not IL-2Rα. These enhanced
in vitro tumor-specific and proliferative responses of γδT cells seen with IL-15 suggest a rational adjuvant imunotherapeutic
use of γδT cells in cancer patients.
Received: 23 January 1998 / Accepted: 20 May 1998 相似文献
8.
Hirohito Kobayashi Yoshimasa Tanaka Junji Yagi Hiroshi Toma Takehiko Uchiyama 《Cancer immunology, immunotherapy : CII》2001,50(3):115-124
Host immune function plays a certain role against the development of renal cell carcinomas (RCCs), but the mechanism is not
entirely understood. Human gamma/delta (γ/δ) T cells defend the body against infection. In this study, we clarify the role
of γ/δ T cells in the surveillance system against RCCs by analyzing the γ/δ T cells in peripheral blood mononucleocytes (PBMs)
and tumor infiltrating lymphocytes (TILs) from 41 patients with RCCs. The results showed that the number of γ/δ T cells expressing
Vγ2 and Vδ2 in variable elements of TCR was elevated in the PBMs in 10 patients, but not in any of 32 healthy individuals.
The proportion of patients with an elevated number of γ/δ T cells (>10%) increased with cancer stage. The level of the γ/δ
T cells decreased after surgery. The γ/δ T cells in the TILs were more activated than those in the PBMs. Evaluation of the
junctional diversity of TCR Vγ2 and Vδ2 chains showed that the increased peripheral blood γ/δ T cells were oligoclonal rather
than polyclonal. Taken together, our findings suggest that γ/δ T cells recognize certain RCC-related antigens and play a role
in the surveillance system against RCCs.
Received: 30 November 2000 / Accepted: 2 January 2001 相似文献
9.
Lang JM Kaikobad MR Wallace M Staab MJ Horvath DL Wilding G Liu G Eickhoff JC McNeel DG Malkovsky M 《Cancer immunology, immunotherapy : CII》2011,60(10):1447-1460
Prior to the advent of VEGF-targeted therapies, renal cell carcinoma (RCC) was among the few solid tumors shown to respond
to cytokine-based therapies such as interleukin-2 (IL-2) and interferon alpha. Previous work has shown that aminobisphosphonates,
including zoledronic acid (ZA), are capable of activating human Vγ9 Vδ2 T cells in vitro, and these cells can be further expanded
with IL-2. Moreover, these Vγ9 Vδ2 T cells have cytolytic activity in vitro to multiple human tumor cell lines. In the current
report, we have conducted a pilot trial in patients with metastatic RCC, evaluating different doses of ZA in combination with
low-dose IL-2 to determine whether combining these agents can promote in vivo proliferation of Vγ9 Vδ2 T cells and elicit
an antitumor response. In 12 patients evaluated, no objective clinical responses were observed by RECIST criteria; however,
two patients experienced prolonged stable disease. A modest increase in Vγ9 Vδ2 T-cell frequency could be detected by Day
8 of therapy in four of the nine patients who received at least one cycle of therapy, but not to the magnitude anticipated
from preclinical models. Repeated administration of IL-2 and ZA resulted in both a diminished in vivo percentage of Vγ9 Vδ2
T cells as well as impaired expansion in vitro after the first cycle of therapy. These results suggest that repeated administration
of IL-2 and ZA, at the doses and schedules used in this trial, may actually inhibit the proliferative capacity of Vγ9 Vδ2
T cell in patients with metastatic RCC. 相似文献
10.
Sandy Pelletier Simon Tanguay Stephen Lee Lakshman Gunaratnam Nathalie Arbour Réjean Lapointe 《Cancer immunology, immunotherapy : CII》2009,58(8):1207-1218
Objectives Patients with renal cell carcinomas (RCC) have few treatment options, underscoring the importance of developing new approaches
such as immunotherapy. However, few tumor associated antigens (TAA), which can be targeted by immunotherapy, have been identified
for this type of cancer. von Hippel-Lindau clear cell RCC (VHL−/−RCC) are characterized by mutations in the VHL tumor suppressor gene. Loss of VHL function causes the overexpression of transforming
growth factor (TGF)-α, leading us to hypothesize that TGF-α could be a potential TAA for immunotherapy of kidney cancer, which
was evaluated in this study.
Methods and results We first confirmed the absent or weak expression of TGF-α in important normal tissues as well as its overexpression in 61%
of renal tumors in comparison to autologous normal kidney tissues. In addition, we demonstrated the immunogenicity of TGF-α,
by expanding many T cell lines specific for certain TGF-α peptides or the mature TGF-α protein, when presented by major histocompatibility
complex (MHC) molecules on the surface of antigen-presenting cells. Interestingly, some of these TGF-α-specific T cells were
polyfunctionals and secreted IFN-γ, TNF-α and IL-2.
Conclusion We have shown that TGF-α is a valid candidate TAA, which should allow the development of a targeted immunotherapy. 相似文献
11.
Clinical strategies to exploit Vγ2Vδ2 T cell responses for immunotherapy are confronted with short-term increases in cell
levels or activity and the development of anergy that reduces the response to therapy with succeeding treatments. We are exploring
strategies to increase the yield and durability of elicited Vγ2Vδ2 T cell responses. One approach focuses on the mammalian
target of rapamycin (mTOR), which is important for regulating T cell metabolism and function. In Vγ2Vδ2 T cells, mTOR phosphorylates
the S6K1 and eIF4EBP1 signaling intermediates after antigen stimulation. Rapamycin inhibited these phosphorylation events
without impacting Akt or Erk activation, even though specific inhibition of Akt or Erk in turn reduced the activation of mTOR.
The effects of rapamycin on the T cell receptor signaling pathway lead to increased proliferation of treated and antigen-exposed
Vγ2Vδ2 cells. Rapamycin altered the phenotype of antigen-specific Vγ2Vδ2 cells by inducing a population shift from CD62L + CD69−
to CD62L-CD69+, higher expression of CD25 or Bcl-2, lower levels of CCR5 and increased resistance to Fas-mediated cellular
apoptosis. These changes were consistent with rapamycin promoting cell activation while decreasing the susceptibility to cell
death that might occur by CCR5 or Fas signaling. Rapamycin treatment during antigen-stimulation of Vγ2Vδ2 T cells may be a
strategy for overcoming current obstacles in tumor immunotherapy. 相似文献
12.
Yuasa T Sato K Ashihara E Takeuchi M Maita S Tsuchiya N Habuchi T Maekawa T Kimura S 《Cancer immunology, immunotherapy : CII》2009,58(4):493-502
Background Superficial bladder cancers are usually managed with transurethral resection followed by the intravesical administration of
Bacillus Calmette-Guerin which requires major histocompatibility complex (MHC) class I expression on cancer cells. Since cancer
cells often loose MHC expression, a novel immunotherapy such as MHC-unrestricted γδ T cell therapy is desired.
Objective To clarify the relationship between the expression of MHC class I and clinicopathological features in bladder cancer patients,
and investigate the effects of the administration of intravesical γδ T cells on bladder cancer.
Methods Samples from 123 patients who had undergone either transurethral resection or radical cystectomies were examined for MHC expression
and the relationship between this and the clinicopathological features was analyzed statistically. The in vitro and in vivo
effects of γδ T cells expanded by zoledronic acid (ZOL) against several types of cancer cell line and an orthotopic bladder
cancer murine model which was pretreated with ZOL were investigated.
Results MHC-diminished superficial bladder cancer was significantly more progressive than MHC-conservative bladder cancer (P = 0.047). In addition, there was a significant association between diminished MHC expression and poor disease free survival
(P = 0.041) and overall survival (P = 0.018) after radical cystectomy. In vitro, all of the cell lines pretreated with 5-μM ZOL showed a marked increase in sensitivity
to lysis by γδ T cells. Moreover, intravesical administration of γδ T cells with 5-μM ZOL significantly demonstrated antitumor
activity against bladder cancer cells in the orthotopic murine model (P < 0.001), resulting in prolonged survival.
Conclusion The present murine model provides a potentially interesting option to develop immunotherapy using γδ T cells for bladder cancer
in human.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
T. Yuasa and K. Sato contributed equally to the study. 相似文献
13.
Kia Joo Puan John Seng Hooi Low Terence Wee Kiat Tan Joseph Tien Seng Wee Eng Huat Tan Kam Weng Fong Eu Tiong Chua Chenggang Jin José-Luis Giner Craig T. Morita Christopher Hood Keng Goh Kam M. Hui 《Cancer immunology, immunotherapy : CII》2009,58(7):1095-1107
Introduction Human Vγ2Vδ2 T cells play important role in immunity to infection and cancer by monitoring self and foreign isoprenoid metabolites
with their γδ T cell antigen receptors. Like CD4 and CD8 αβ T cells, adult peripheral Vγ2Vδ2 T cells represent a pool of heterogeneous
cells with distinct functional capabilities.
Purpose The aim of this study was to characterize the phenotypes and functions of various Vγ2Vδ2 T cell subsets in patients with nasopharyngeal
carcinoma (NPC). We sought to develop a better understanding of the role of these cells during the course of disease and to
facilitate the development of immunotherapeutic strategies against NPC.
Results Although similar total percentages of peripheral blood Vγ2Vδ2 T cells were found in both NPC patients and normal donors, Vγ2Vδ2
T cells from NPC patients showed decreased cytotoxicity against tumor cells whereas Vγ2Vδ2 T cells from normal donors showed
potent cytotoxicity. To investigate further, we compared the phenotypic characteristics of Vγ2Vδ2 T cells from 96 patients
with NPC and 54 healthy controls. The fraction of late effector memory Vγ2Vδ2 T cells (TEM RA) was significantly increased in NPC patients with corresponding decreases in the fraction of early memory Vγ2Vδ2 T cells
(TCM) compared with those in healthy controls. Moreover, TEM RA and TCM Vγ2Vδ2 cells from NPC patients produced significantly less IFN-γ and TNF-α, potentially contributing to their impaired cytotoxicity.
Radiotherapy or concurrent chemo-radiotherapy further increased the TEM RA Vγ2Vδ2 T cell population but did not correct the impaired production of IFN-γ and TNF-α observed for TEM RA Vγ2Vδ2 T cells.
Conclusion We have identified distinct alterations in the Vγ2Vδ2 T cell subsets of patients with NPC. Moreover, the overall cellular
effector function of γδ T cells is compromised in these patients. Our data suggest that the contribution of Vγ2Vδ2 T cells
to control NPC may depend on the activation state and differentiation of these cells.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
14.
Hollie J. Pegram Nicole M. Haynes Mark J. Smyth Michael H. Kershaw Phillip K. Darcy 《Cancer immunology, immunotherapy : CII》2010,59(8):1235-1246
Natural killer (NK) cells represent a promising cell type to utilize for effective adoptive immunotherapy. However, little
is known about the important cytolytic molecules and signaling pathways used by NK cells in the adoptive transfer setting.
To address this issue, we developed a novel mouse model to investigate the trafficking and mechanism of action of these cells.
We demonstrate that methylcholanthrene-induced RKIK sarcoma cells were susceptible to NK cell-mediated lysis in vitro and
in vivo following adoptive transfer of NK cells in C57BL/6 RAG-2−/−γc−/− mice. Cytotoxic molecules perforin, granzymes B and M as well as the death ligand TRAIL and pro-inflammatory cytokine IFN-γ
were found to be important in the anti-tumor effect mediated by adoptively transferred NK cells. Importantly, we demonstrate
that adoptively transferred NK cells could traffic to the tumor site and persisted in vivo which correlated with the anti-tumor
effect observed. Overall, the results of this study have important implications for enhancing NK cell-based immunotherapies. 相似文献
15.
Hye Won Lee Chanho Park Je-Gun Joung Minyong Kang Yun Shin Chung Won Joon Oh Seon-Yong Yeom Woong-Yang Park Tae Jin Kim Seong Il Seo 《Current issues in molecular biology》2021,43(1):226
Due to the highly immunogenic nature of renal cell carcinoma (RCC), the tumor microenvironment (TME) is enriched with various innate and adaptive immune subsets. In particular, gamma-delta (γδ) T cells can act as potent attractive mediators of adoptive cell transfer immunotherapy because of their unique properties such as non-reliance on major histocompatibility complex expression, their ability to infiltrate human tumors and recognize tumor antigens, relative insensitivity to immune checkpoint molecules, and broad tumor cytotoxicity. Therefore, it is now critical to better characterize human γδ T-cell subsets and their mechanisms in RCCs, especially the stage of differentiation. In this study, we aimed to identify γδ T cells that might have adaptive responses against RCC progression. We characterized γδ T cells in peripheral blood and tumor-infiltrating lymphocytes (TILs) in freshly resected tumor specimens from 20 RCC patients. Furthermore, we performed a gene set enrichment analysis on RNA-sequencing data from The Cancer Genome Atlas (TCGA) derived from normal kidneys and RCC tumors to ascertain the association between γδ T-cell infiltration and anti-cancer immune activity. Notably, RCC-infiltrating CD3low Vγ9Vδ1 T cells with a terminally differentiated effector memory phenotype with up-regulated activation/exhaustion molecules were newly detected as predominant TILs, and the cytotoxic activity of these cells against RCC was confirmed in vitro. In an additional analysis of the TCGA RCC dataset, γδ T-cell enrichment scores correlated strongly with those for CTLs, Th1 cells, “exhausted” T cells, and M1 macrophages, suggesting active involvement of γδ T cells in anti-tumor rather than pro-tumor activity, and Vδ1 cells were more abundant than Vδ2 or Vδ3 cells in RCC tumor samples. Thus, we posit that Vγ9Vδ1 T cells may represent an excellent candidate for adoptive immunotherapy in RCC patients with a high risk of relapse after surgery. 相似文献
16.
Schuetz F Ehlert K Ge Y Schneeweiss A Rom J Inzkirweli N Sohn C Schirrmacher V Beckhove P 《Cancer immunology, immunotherapy : CII》2009,58(6):887-900
Background Breast cancer patients frequently harbour tumour-reactive memory T cells in their bone marrow (BM) but not in the blood. After
reactivation ex-vivo these cells rejected autologous breast tumours in xenotransplanted mice demonstrating therapeutic potential
upon reactivation and mobilization into the blood. We conducted a clinical pilot study on metastasized breast cancer patients
to investigate if ex-vivo reactivation of tumour-reactive BM memory T cells and their adoptive transfer is feasible and increases
the frequencies of tumour-reactive T cells in the blood.
Methods The study protocol involved one transfusion of T cells which were reactivated in vitro with autologous dendritic cells pulsed
with lysate of MCF7 breast cancer cells as source of tumour antigens. Immunomonitoring included characterization of T cell
activation in vitro and of tumour-specific T cells in the blood by interferon (IFN)-γ ELISPOT assay, HLA-tetramers and antigen-induced
interleukin (IL)-4 secretion.
Results Twelve patients with pre-existing tumour-reactive BM memory T cells were included into the study. In all cases, the treatment
was feasible and well tolerated. Six patients (responders) showed by ELISPOT assay de-novo tumour antigen-specific, IFN-γ-secreting
T cells in the blood after 7 days. In contrast, non responders showed in the blood tumour antigen-induced IL-4 responses.
All responders received more than 6.5 × 103 tumour-reactive T cells. In contrast, all non responders received lower numbers of tumour antigen-reactive T cells. This
was associated with reduced activation of memory T cells in activation cultures, increased amounts of CD4+ CD25high regulatory T cells in the BM and increased tumour antigen-dependent IL-10 secretion. The latter was prevented by preceding
depletion of regulatory T cells suggesting that regulatory T cells in the BM can inhibit reactivation of tumour-specific T
cells.
Conclusion Taken together, adoptive transfer of ex-vivo re-stimulated tumour-reactive memory T cells from BM of metastasized breast cancer
patients can induce the presence of tumour antigen-reactive type-1 T cells in the peripheral blood.
Florian Schuetz and Katrin Ehlert contributed equally to the study. 相似文献
17.
Giovanni Triolo Antonina Accardo-Palumbo Francesco Dieli Francesco Ciccia Angelo Ferrante Ennio Giardina Di Caterina Sano Giuseppe Licata 《Arthritis research & therapy》2003,5(5):R262
Beh?et's disease is a multisystem disease in which there is evidence of immunological dysregulation. It has been proposed
that γ/δ T cells are involved in its pathogenesis. The aim of the present study was to assess the capacity of γ/δ T cells
with phenotype Vγ9/Vδ2, from a group of Italian patients with Beh?et's disease, to proliferate in the presence of various
phosphoantigens and to express tumour necrosis factor (TNF) and IL-12 receptors. Twenty-five patients and 45 healthy individuals
were studied. Vγ9/Vδ2 T cells were analyzed by fluorescence activated cell sorting, utilizing specific monoclonal antibodies.
For the expansion of Vγ9/Vδ2 T cells, lymphocytes were cultured in the presence of various phosphoantigens. The expression
of TNF receptor II and IL-12 receptor β1 was evaluated with the simultaneous use of anti-TNF receptor II phycoerythrin-labelled (PE) or anti-IL-12 receptor β1 PE and anti-Vδ2 T-cell receptor fluorescein isothiocyanate. There was a certain hierarchy in the response of Vγ9/Vδ2 T cells
toward the different phosphoantigens, with the highest expansion factor obtained with dimethylallyl pyrophosphate and the
lowest with xylose 1P. The expansion factor was fivefold greater in patients with active disease than in those with inactive
disease or in control individuals. TNF receptor II and IL-12 receptor β1 expressions were increased in both patients and control individuals. The proportion of Vγ9/Vδ2 T cells bearing these receptors
was raised in active disease when Vγ9/Vδ2 T cells were cultured in the presence of dimethylallyl pyrophosphate. These results
indicate that Vγ9/Vδ2 T cell activation is correlated with disease progression and probably involved in the pathogenesis. 相似文献
18.
Characterization of the γδ T cell response to acute leukemia 总被引:1,自引:0,他引:1
Meeh PF King M O'Brien RL Muga S Buckhalts P Neuberg R Lamb LS 《Cancer immunology, immunotherapy : CII》2006,55(9):1072-1080
Background: Previous work from our center has suggested a correlation between increased donor-derived Vδ1+ γδ T cells and long-term relapse-free survival following bone marrow transplantation for leukemia. Questions remain, however, as to whether this observation can be explained by a γδ T cell-based immune response against primary leukemia. Methods: We examined γδ T cell receptor (TCR) phenotype, cell proliferation, and cytolytic activity following culture with irradiated primary leukemia blasts from a haploidentical first-degree relative. Subsequently, we also studied the γδ TCR phenotype and complimentarity determining region 3 (CDR3) cDNA sequences from 17 newly diagnosed leukemia patients. Results: In 17/28 (61%) of in vitro cultures, γδ T cells proliferated in culture with primary blasts. Vδ1+ T cells were proportionally increased in all cultures and were the predominant cell population in 6/17. In the 7 cultures where cytotoxicity could be assessed, 6 (86%) showed some degree of cytotoxicity to the primary leukemia. Vδ1+ T cells were also the predominant γδ T cell subtype in pre-treatment leukemia patients principally due to loss of Vδ2+ T cells rather than expansion of Vδ1+ cells. The Vδ1 CDR3-region cDNA sequence from these patients revealed exclusive use of the Jδ1 constant region and sequence conservation in 4/11 patients. Conclusions: γδ T cells exhibit an in vitro response to primary leukemia blasts that is manifested by proliferation, an increased proportion of Vδ1+ T cells, and cytotoxicity to the primary leukemia blasts. The Vδ1+ T cell population is also predominant in newly diagnosed leukemia patients likely due to a loss of circulating Vδ2+ T cells. A small proportion of newly diagnosed patients showed Vδ1 CDR3 region similarity. These findings suggest a role for γδ T cells in the immune response to leukemia.Paul F. Meeh and Michelle King are contributed equally to this work. 相似文献
19.
Turin I Pedrazzoli P Tullio C Montini E La Grotteria MC Schiavo R Perotti C Locatelli F Carretto E Maccario R Siena S Montagna D 《Cytotherapy》2007,9(5):499-507
BACKGROUND: The adoptive transfer of ex vivo-induced tumor-specific T-cell lines provides a promising approach for cancer immunotherapy. We have demonstrated previously the feasibility of inducing in vitro long-term anti-tumor cytotoxic T-cell (CTL) lines directed against different types of solid tumors derived from both autologous and allogeneic PBMC. We have now investigated the possibility of producing large amounts of autologous anti-tumor CTL, in compliance with good manufacturing practices, for in vivo use. METHODS: Four patients with advanced solid tumors (two sarcoma, one renal cell cancer and one ovarian cancer), who had received several lines of anticancer therapy, were enrolled. For anti-tumor CTL induction, patient-derived CD8-enriched PBMC were stimulated with DC pulsed with apoptotic autologous tumor cells (TC) as the source of tumor Ag. CTL were then restimulated in the presence of TC and expanded in an Ag-independent way. RESULTS: Large amounts of anti-tumor CTL (range 14-20 x 10(9)), which displayed high levels of cytotoxic activity against autologous TC, were obtained in all patients by means of two-three rounds of tumor-specific stimulation and two rounds of Ag-independent expansion, even when a very low number of viable TC was available. More than 90% of effector cells were CD3(+) CD8(+) T cells, while CD4(+) T lymphocytes and/or NK cells were less than 10%. DISCUSSION: Our results demonstrate the feasibility of obtaining large quantities of anti-tumor specific CTL suitable for adoptive immunotherapy approaches. 相似文献
20.
BACKGROUND: DC are potent APC that can activate both CD4 and CD8 T cells in vitro and in vivo. Although the efficacy of DC-based cancer vaccines is currently being evaluated in clinical trials, the systemic immune suppression in cancer patients negatively impacts the clinical benefit of this therapeutic approach. Therefore, in this study we tested the feasibility and anti-tumor effect of adoptive immunotherapy using in vitro-activated CD62L(low) lymph node cells that were isolated from DC-vaccinated draining lymph nodes (VDLN). METHODS: DC were prepared from BM cells and loaded with tumor lysate for inoculating into naive mice. Subsequently, the VDLN were removed and CD62L(low) cells in the VDLN population isolated, expanded in vitro by 5-day culture with IL-2 and immobilized anti-CD3 stimulation, then injected into mice with established pulmonary tumors. Eighteen days after treatment, mice were killed in order to enumerate pulmonary tumor nodes. RESULTS: DC phagocytosed the tumor lysate efficiently and induced detectable T-cell responses and significant cell expansion in the draining lymph nodes. After induction of maturation by LPS treatment, DC expressed higher levels of CD40, CD86 and MHC class II molecules. When CD62L(low) VDLN cells that had been isolated and expanded in vitro were transferred into tumor-bearing mice, as few as 3 x 10(6) cells were able to cure metastatic pulmonary tumors in vivo. DISCUSSION: DC-based VDLN T cells are an important source of anti-tumor effector for adoptive immunotherapy. This study provides a novel and an effective protocol using T-cell adoptive immunotherapy for application in cancer patients; therefore, clinical trials based on this protocol may be warranted. 相似文献