共查询到20条相似文献,搜索用时 15 毫秒
1.
Jessica Ann Chacon Richard C. Wu Pariya Sukhumalchandra Jeffrey J. Molldrem Amod Sarnaik Shari Pilon-Thomas Jeffrey Weber Patrick Hwu Laszlo Radvanyi 《PloS one》2013,8(4)
Adoptive T-cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) can induce tumor regression in up to 50% or more of patients with unresectable metastatic melanoma. However, current methods to expand melanoma TIL, especially the “rapid expansion protocol” (REP) were not designed to enhance the generation of optimal effector-memory CD8+ T cells for infusion. One approach to this problem is to manipulate specific co-stimulatory signaling pathways to enhance CD8+ effector-memory T-cell expansion. In this study, we determined the effects of activating the TNF-R family member 4-1BB/CD137, specifically induced in activated CD8+ T cells, on the yield, phenotype, and functional activity of expanded CD8+ T cells during the REP. We found that CD8+ TIL up-regulate 4-1BB expression early during the REP after initial TCR stimulation, but neither the PBMC feeder cells in the REP or the activated TIL expressed 4-1BB ligand. However, addition of an exogenous agonistic anti-4-1BB IgG4 (BMS 663513) to the REP significantly enhanced the frequency and total yield of CD8+ T cells as well as their maintenance of CD28 and increased their anti-tumor CTL activity. Gene expression analysis found an increase in bcl-2 and survivin expression induced by 4-1BB that was associated with an enhanced survival capability of CD8+ post-REP TIL when re-cultured in the absence or presence of cytokines. Our findings suggest that adding an agonistic anti-4-1BB antibody during the time of TIL REP initiation produces a CD8+ T cell population capable of improved effector function and survival. This may greatly improve TIL persistence and anti-tumor activity in vivo after adoptive transfer into patients. 相似文献
2.
Michael Rosenzweig Douglas F. Marks Donna Hempel R. Paul Johnson 《Journal of medical primatology》1996,25(3):192-200
Abstract: Stable introduction of therapeutic genes into hematopoietic stem cells has the potential to reconstitute immunity in individuals with HIV infection. However, many important questions regarding the safety and efficacy of this approach remain unanswered and may be addressed in a non-human primate model. To facilitate evaluation of expression of foreign genes in T cells derived from transduced hematopoietic progenitor cells, we have established a culture system that supports the differentiation of rhesus macaque and human CD34+ bone marrow derived cells into mature T cells. Thymic stromal monolayers were prepared from the adherent cell fraction of collagenase digested fetal or neonatal thymus. After 10–14 days, purified rhesus CD34+ bone marrow-derived cells cultured on thymic stromal monolayers yielded CD3+CD4+CD8+, CD3+CD4+CD8?, and CD3+CD4?CD8+ cells. Following stimulation with mitogens, these T cells derived from CD34+ cells could be expanded over 1,000-fold and maintained in culture for up to 20 weeks. We next evaluated the ability of rhesus CD34+ cells transduced with a retroviral vector containing the marker gene neo to undergo in vitro T cell differentiation. CD34+ cells transduced in the presence of bone marrow stroma and then cultured on rhesus thymic stroma resulted in T cells containing the retroviral marker gene. These studies should facilitate both in vitro and in vivo studies of hematopoietic stem cell therapeutic strategies for AIDS. 相似文献
3.
Ursula Elsässer-Beile Thomas Grussenmeyer Dorothee Gierschner Barbara Schmoll Wolfgang Schultze-Seemann Ulrich Wetterauer Jürgen Schulte Mönting 《Cancer immunology, immunotherapy : CII》1999,48(4):204-208
The mRNA expression of Th1 and Th2 cytokines was compared in freshly isolated CD3+ tumor-infiltrating lymphocytes (CD3+ TIL) and in autologous CD3+ peripheral blood lymphocytes (CD3+ PBL) obtained simultaneously from 20 patients with renal cell carcinomas (RCC). In addition cytokine expression was compared
in CD4+ TIL and CD8+ TIL from another group of 20 patients with RCC. TIL were isolated from mechanically disaggregated tumor material and PBL
from peripheral blood by gradient centrifugation and subsequent selection with anti-CD3, anti-CD4 or anti-CD8 magnetic beads.
In these pure lymphocyte preparations the constitutive expression of interleukin-1 (IL-1), IL-2, IL-10, interferon γ (IFN),
and tumor necrosis factor α (TNF) was determined by using a polymerase-chain-reaction-assisted mRNA amplification assay. In
the CD3+ TIL, levels of mRNA for IFN, IL-10, IL-1 and TNF were significantly higher than in the autologous CD3+ PBL whereas IL-2 expression was rather low and did not differ in the two populations. Comparison of cytokine mRNA expression
in CD4+ TIL and simultaneously obtained CD8+ TIL revealed a significantly higher expression of IFN in the CD8+ cells. These data reflect an in vivo activation of RCC-infiltrating lymphocytes at the mRNA level with respect to the Th1
as well as the Th2 immune response. Th1 activation seems to be most evident in the CD8+ TIL.
Received: 14 January 1999 / Accepted: 30 April 1999 相似文献
4.
Requirement of monocytes and T-helper cells during development of tumor cell cytotoxicity in targeted T cells 总被引:1,自引:0,他引:1
Karine A. Smans Marc F. Hoylaerts Marc E. De Broe 《Cancer immunology, immunotherapy : CII》1994,38(1):43-52
In cocultures of human plancental alkaline phosphatase(PLAP)-positive MO4 tumor cells and human peripheral blood mononuclear cells (PBMC), also containing a heteroconjugate (7E8-OKT3) synthesized between the anti-PLAP monoclonal antibody 7E8 and the anti-CD3 antibody OKT3, and supplemented with low levels of recombinant interleukin-2 (rIL-2), T cells are progressively activated, resulting in tumor cell lysis. To unravel the contribution of PBMC subsets to the generation of this targetable cytotoxicity, PBMC subsets were studied after their isolation by cell sorting, either from fresh PBMC or from PBMC peractivated with OKTe3 and rIL-2. Whereas no targetable cytotoxicity was found in Fc-receptor-bearing CD3-cells, tumor cells were lysed by CD3+ T cells (mostly CD8+) isolated from pre-activated PBMC. When isolated from fresh PBMC, neither the CD8+ T cell subset, nor the total CD3+ T cell population developed significant targetable cytotoxicity, even in the presence of rIL-2. Thus, additional cell types are essential for the CD8+ T cell activation. Indeed. CD4+ T cells isolated from pre-activated but not from fresh PBMC were capable of eliciting cytotoxicity in fresh CD8+ T cells. The non-targeted monocytes were found to be the activators of the CD4+ T cells. In summary, targeting T cells to the surface of a tumor cell is not sufficientper se to achieve activation and lysis. The progressive tumor cell lysis by targeted T cells seems to be initiated by non-targeted monocytes activating CD4+ T cells, these cells in turn promoting CD8+ T cell activation, necessary for the development of cytotoxicity. 相似文献
5.
Elizabeth M. Kraakman Ronald E. Bontrop Reno Groenesteln Margreet Jonker Joost J. Haaijman Bert A. t Hart 《Journal of medical primatology》1995,24(4):306-313
Abstract: Rhesus monkeys show a high proliferative T cell response to the bacterial exotoxin SLO without prior immunization. The present study was undertaken to characterize this naturally present SLO-responsiveness with particular emphasis on CD4+ve reactive T cells. It is demonstrated that the frequency of SLO-reactive cells in the circulation ranges between 1 in 75 and 1 in 610 CD4+ve T cells as determined with limiting dilution analysis. It is also shown that induction of a good proliferative response requires Mhc-DR matching between T cell and the antigen presenting cells (APC). Stable and DR-restricted SLO-specific CD4+ve T cell lines were generated from CD8 depleted peripheral blood mononuclear cells (PBMC). The SLO-reactive CD4+ve cell lines are tentatively characterized as Thl-like based on the predominant production of interferon-gamma (IFN-γ) over IL-4, although this seems contradicted by the IL-4 dependent growth of the lines. 相似文献
6.
Parviz Fallah Ehsan Arefian Mahmood Naderi Seyed Hamid Aghaee-Bakhtiari Amir Atashi Katayoun Ahmadi Abbas Shafiee Masoud Soleimani 《Molecular biology reports》2013,40(8):4713-4719
MicroRNAs control the genes involved in hematopoietic stem cell (HSCs) survival, proliferation and differentiation. The over-expression of miR-146 and miR-150 has been reported during differentiation of HSCs into T-lymphoid lineage. Therefore, in this study we evaluated the effect of their over-expression on CD133+ cells differentiation to T cells. miR-146a and miR-150 were separately and jointly transduced to human cord blood derived CD133+ cells (>97 % purity). We used qRT-PCR to assess the expression of CD2, CD3ε, CD4, CD8, CD25, T cell receptor alpha (TCR-α) and Ikaros genes in differentiated cells 4 and 8 days after transduction of the miRNAs. Following the over-expression of miR-146a, significant up-regulation of CD2, CD4, CD25 and Ikaros genes were observed (P < 0.01). On the other hand, over-expression of miR-150 caused an increase in the expression of Ikaros, CD4, CD25 and TCR-α. To evaluate the combinatorial effect of miR-146a and miR-150, transduction of both miRNAs was concurrently performed which led to increase in the expression of Ikaros, CD4 and CD3 genes. In conclusion, it seems that the effect of miR-150 and miR-146a on the promotion of T cell differentiation is time-dependant. Moreover, miRNAs could be used either as substitutes or complements of the conventional differentiation protocols for higher efficiency. 相似文献
7.
Efficient expansion of tumor-infiltrating lymphocytes from solid tumors by stimulation with combined CD3 and CD28 monoclonal antibodies 总被引:3,自引:0,他引:3
Marcel J. Flens Wilhelmina M. C. Mulder Herman Bril Mary B. E. von Blomberg van de Flier Rik J. Scheper René A. W. van Lier 《Cancer immunology, immunotherapy : CII》1993,37(5):323-328
Combined CD3 and CD28 monoclonal antibodies (mAb) may initiate efficient activation and expansion of tumor-infiltrating lymphocytes (TIL). In this study we compared phenotypical and functional characteristics of TIL from a group of 17 solid human tumors, stimulated either by high-dose recombinant interleukin 2 (rIL-2, 1000 IU/ml) or by a combination of anti-CD3 and anti-CD28 monoclonal antibodies in the presence of low-dose rIL-2 (10 IU/ml). Compared to activation with high-dose rIL-2, stimulation of TIL with CD3/CD28 mAb induced significantly stronger proliferation and yielded higher levels of cell recovery on day 14. Following the CD3/CD28 protocol, expansion of an almost pure population of CD3+ cells was obtained. Whereas CD4+ cells dominated in the first week of culturing, within 4 weeks the CD8+ population increased to over 90%. The specific capacity to kill autologous tumor cells was not increased as compared to the high-dose rIL-2 protocol, but all cultures showed high cytotoxic T cell activity as measured in a CD3-mAb-mediated redirected kill assay. These studies show that combined CD3 and CD28 mAb are superior to rIL-2 with respect to the initiation of expansion of CD8+ cytolytic TIL from solid tumors. Stimulation with specific tumor antigens at a later stage of culturing may further augment the expansion of tumor-specific cytolytic T cells. 相似文献
8.
Rapid G0/1 transition and cell cycle progression in CD8+ T cells compared to CD4+ T cells following in vitro stimulation
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Takuya Mishima Shotaro Fukaya Shoko Toda Yoshiaki Ando Tsukasa Matsunaga Manabu Inobe 《Microbiology and immunology》2017,61(5):168-175
T‐cell population consists of two major subsets, CD4+ T cells and CD8+ T cells, which can be distinguished by the expression of CD4 or CD8 molecules, respectively. Although they play quite different roles in the immune system, many of their basic cellular processes such as proliferation following stimulation are presumably common. In this study, we have carefully analyzed time–course of G0/1 transition as well as cell cycle progression in the two subsets of quiescent T‐cell population following in vitro growth stimulation. We found that CD8+ T cells promote G0/1 transition more rapidly and drive their cell cycle progression faster compared to CD4+ T cells. In addition, expression of CD25 and effects of its blockade revealed that IL‐2 is implicated in the rapid progression, but not the earlier G0/1 transition, of CD8+ T cells. 相似文献
9.
10.
11.
The CD4+AT2R+ T cell subpopulation improves post‐infarction remodelling and restores cardiac function
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Anna Skorska Stephan von Haehling Marion Ludwig Cornelia A. Lux Ralf Gaebel Gabriela Kleiner Christian Klopsch Jun Dong Caterina Curato Wassim Altarche‐Xifró Svetlana Slavic Thomas Unger Robert David 《Journal of cellular and molecular medicine》2015,19(8):1975-1985
Myocardial infarction (MI) is a major condition causing heart failure (HF). After MI, the renin angiotensin system (RAS) and its signalling octapeptide angiotensin II (Ang II) interferes with cardiac injury/repair via the AT1 and AT2 receptors (AT1R, AT2R). Our study aimed at deciphering the mechanisms underlying the link between RAS and cellular components of the immune response relying on a rodent model of HF as well as HF patients. Flow cytometric analyses showed an increase in the expression of CD4+ AT2R+ cells in the rat heart and spleen post‐infarction, but a reduction in the peripheral blood. The latter was also observed in HF patients. The frequency of rat CD4+ AT2R+ T cells in circulating blood, post‐infarcted heart and spleen represented 3.8 ± 0.4%, 23.2 ± 2.7% and 22.6 ± 2.6% of the CD4+ cells. CD4+ AT2R+ T cells within blood CD4+ T cells were reduced from 2.6 ± 0.2% in healthy controls to 1.7 ± 0.4% in patients. Moreover, we characterized CD4+ AT2R+ T cells which expressed regulatory FoxP3, secreted interleukin‐10 and other inflammatory‐related cytokines. Furthermore, intramyocardial injection of MI‐induced splenic CD4+ AT2R+ T cells into recipient rats with MI led to reduced infarct size and improved cardiac performance. We defined CD4+ AT2R+ cells as a T cell subset improving heart function post‐MI corresponding with reduced infarction size in a rat MI‐model. Our results indicate CD4+ AT2R+ cells as a promising population for regenerative therapy, via myocardial transplantation, pharmacological AT2R activation or a combination thereof. 相似文献
12.
The function of T cell subsets in tumor-bearing mice was examined using an in vitro culture system of anti-(sheep red blood cell) antibody production, which is known to be dependent on T cells. The helper function of T cells of fibrosarcoma-MethA-bearing mice in antibody production decreased with the tumor stage of the mice. T cells were separated into CD4+ and CD8+ cells for further analysis of T cell subsets by the panning method using monoclonal antibodies. The helper function of CD4+ T cells in antibody production began to decrease significantly in tumor-bearing mice 1 week after the tumor transplantation. On the other hand, the suppressive function of CD8+ T cells was retained and had not decreased in the mice even 3 weeks after the transplantation. The same changes in function of CD4+ and CD8+ T cells were also observed in Methl-bearing mice. These results suggested that this tumor-associated immunosuppression in antibody production is attributable to the decrease in helper activity of CD4+ T cells and the maintenance of the suppressive activity of CD8+ T cells. 相似文献
13.
Naoya Uchida Matthew M. Hsieh Charlotte Platner Yogen Saunthararajah John F. Tisdale 《PloS one》2014,9(8)
Efficient ex
vivo transduction of hematopoietic stem cells (HSCs) is encumbered by differentiation which reduces engraftment. We hypothesized that inhibiting DNA methyltransferase with decitabine would block differentiation of transduced CD34+ cells under cytokine stimulation and thus improve transduction efficiency for engrafting HSCs. Human CD34+ cells in cytokine-containing media were treated with or without decitabine for 24 or 48 hours, and then these cells were transduced with a GFP-expressing lentiviral vector. Utilizing decitabine pre-treatment for 48 hours, we observed an equivalent percentage of successfully transduced cells (GFP-positivity) and a higher percentage of cells that retained CD34 positivity, compared to no decitabine exposure. Cell proliferation was inhibited after decitabine exposure. Similar results were observed among CD34+ cells from six different donors. Repopulating activity was evaluated by transplantation into NOD/SCID/IL2Rγnull mice and demonstrated an equivalent percentage of GFP-positivity in human cells from decitabine-treated samples and a trend for higher human cell engraftment (measured 20–24 weeks after transplantation), compared to no decitabine exposure. In conclusion, ex
vivo decitabine exposure inhibits both differentiation and proliferation in transduced human CD34+ cells and modestly increases the engraftment ability in xenograft mice, while the transduction efficiency is equivalent in decitabine exposure, suggesting improvement of lentiviral transduction for HSCs. 相似文献
14.
Dae-Hee Sohn Hyun-Jung Sohn Hyun-Joo Lee Seon-Duk Lee Sueon Kim Seung-Joo Hyun Hyun-Il Cho Seok-Goo Cho Suk-Kyeong Lee Tai-Gyu Kim 《PloS one》2015,10(5)
An EBV-specific cellular immune response is associated with the control of EBV-associated malignancies and lymphoproliferative diseases, some of which have been successfully treated by adoptive T cell therapy. Therefore, many methods have been used to measure EBV-specific cellular immune responses. Previous studies have mainly used autologous EBV-transformed B-lymphoblastoid cell lines (B-LCLs), recombinant viral vectors transfected or peptide pulsed dendritic cells (DCs) as stimulators of CD8+ and CD4+ T lymphocytes. In the present study, we used an interferon-γ (IFN-γ) enzyme-linked immunospot (ELISPOT) assay by using isolated CD8+ and CD4+ T cells stimulated with mRNA-transfected DCs. The frequency of latent membrane protein 1 (LMP1)-specific IFN-γ producing CD4+ T cells was significantly higher than that of LMP2a. The frequency of IFN-γ producing CD4+ T cells was significantly correlated with that of CD8+ T cells in LMP1-specific immune responses (r = 0.7187, Pc < 0.0001). To determine whether there were changes in LMP1- or LMP2a-specific immune responses, subsequent peripheral blood mononuclear cells (PBMCs) samples were analyzed. Significant changes were observed in 5 of the 10 donors examined, and CD4+ T cell responses showed more significant changes than CD8+ T cell responses. CD8+ and CD4+ T cells from EBV-seropositive donors secreted only the Th1 cytokines IFN-γ, TNF-α, and IL-2, while Th2 (IL-4) and Th17 (IL-17a) cytokines were not detected. CD4+ T cells secreted significantly higher cytokine levels than did CD8+ T cells. Analysis of EBV-specific T cell responses using autologous DCs transfected with mRNA might provide a comprehensive tool for monitoring EBV infection and new insights into the pathogenesis of EBV-associated diseases. 相似文献
15.
Role of T‐bet,the master regulator of Th1 cells,in the cytotoxicity of murine CD4+ T cells
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Koji Eshima Kana Misawa Chihiro Ohashi Kazuya Iwabuchi 《Microbiology and immunology》2018,62(5):348-356
16.
Peter Lamprecht Anika Erdmann Antje Mueller Elena Csernok Eva Reinhold-Keller Konstanze Holl-Ulrich Alfred C Feller Hilke Bruehl Wolfgang L Gross 《Arthritis research & therapy》2002,5(1):R25-7
Memory T cells display phenotypic heterogeneity. Surface antigens previously regarded as exclusive markers of naive T cells, such as L-selectin (CD62L), can also be detected on some memory T cells. Moreover, a fraction of CD45RO+ (positive for the short human isoform of CD45) memory T cells reverts to the CD45RA+ (positive for the long human isoform of CD45) phenotype. We analyzed patients with biopsy-proven localized Wegener's granulomatosis (WG) (n = 5), generalized WG (n = 16) and age- and sex-matched healthy controls (n = 13) to further characterize memory T cells in WG. The cell-surface expression of CD45RO, CD45RA, CD62L, CCR3, CCR5 and CXCR3 was determined on blood-derived T cells by four-color flow cytometric analysis. The fractions of CCR5+ and CCR3+ cells within the CD4+CD45RO+ and CD8+CD45RO+ memory T cell populations were significantly expanded in localized and generalized WG. The mean percentage of Th1-type CCR5 expression was higher in localized WG. Upregulated CCR5 and CCR3 expression could also be detected on a fraction of CD45RA+ T cells. CD62L expression was seen on approximately half of the memory T cell populations expressing chemokine receptors. This study demonstrates for the first time that expression of the inducible inflammatory chemokine receptors CCR5 and CCR3 on CD45RO+ memory T cells, as well as on CD45RA+ T cells ('revertants'), contributes to phenotypic heterogeneity in an autoimmune disease, namely WG. Upregulated CCR5 and CCR3 expression suggests that the cells belong to the effector memory T cell population. CCR5 and CCR3 expression on CD4+ and CD8+ memory T cells indicates a potential to respond to chemotactic gradients and might be important in T cell migration contributing to granuloma formation and vasculitis in WG. 相似文献
17.
Butler MO Imataki O Yamashita Y Tanaka M Ansén S Berezovskaya A Metzler G Milstein MI Mooney MM Murray AP Mano H Nadler LM Hirano N 《PloS one》2012,7(1):e30229
Background
Using in vivo mouse models, the mechanisms of CD4+ T cell help have been intensively investigated. However, a mechanistic analysis of human CD4+ T cell help is largely lacking. Our goal was to elucidate the mechanisms of human CD4+ T cell help of CD8+ T cell proliferation using a novel in vitro model.Methods/Principal Findings
We developed a genetically engineered novel human cell-based artificial APC, aAPC/mOKT3, which expresses a membranous form of the anti-CD3 monoclonal antibody OKT3 as well as other immune accessory molecules. Without requiring the addition of allogeneic feeder cells, aAPC/mOKT3 enabled the expansion of both peripheral and tumor-infiltrating T cells, regardless of HLA-restriction. Stimulation with aAPC/mOKT3 did not expand Foxp3+ regulatory T cells, and expanded tumor infiltrating lymphocytes predominantly secreted Th1-type cytokines, interferon-γ and IL-2. In this aAPC-based system, the presence of autologous CD4+ T cells was associated with significantly improved CD8+ T cell expansion in vitro. The CD4+ T cell derived cytokines IL-2 and IL-21 were necessary but not sufficient for this effect. However, CD4+ T cell help of CD8+ T cell proliferation was partially recapitulated by both adding IL-2/IL-21 and by upregulation of IL-21 receptor on CD8+ T cells.Conclusions
We have developed an in vitro model that advances our understanding of the immunobiology of human CD4+ T cell help of CD8+ T cells. Our data suggests that human CD4+ T cell help can be leveraged to expand CD8+ T cells in vitro. 相似文献18.
Cytotoxic T cells infiltrating a glioma express an aberrant phenotype that is associated with decreased function and apoptosis 总被引:5,自引:0,他引:5
In this study, we report on novel alterations found in rat intracranial (i.c.) tumor-infiltrating T lymphocytes (TIL) that
are indicative of T cell defects and death. FACS analysis showed that the cytotoxic T cells (CTL) infiltrating rat T9.F gliomas
were CD3ɛ+, αβTCR+, CD8α
+, but CD8β
−. These lymphocytes also stained positive for the B cell-specific marker, CD45RA, as well as Annexin-V, signifying apoptotic
changes. Functional and biochemical analyses were performed to assess whether the aberrant phenotype was linked to other defects.
When CD8α
+ TIL were purified and stimulated in vitro, their proliferative capacity was markedly diminished in comparison with CD3+CD8α
+CD8β
+ T cells isolated from the spleens of naive, non tumor-bearing rats. Furthermore, the mean fluorescence intensity of surface
CD3ɛ was dramatically reduced in the CD3+CD8α
+CD8β
− TIL population as compared with CD3+CD8α
+CD8β
+ TIL from the same tumor-bearing animal. Biochemical studies revealed that the expression of TCRζ and LAT were reduced in
lysates generated from CD8α-purified TIL with respect to CD8α-purified T cells from naive spleen. We believe that these degenerative changes are reflective of chronic T cell receptor
ligation, because in vitro culture of rat splenocytes or purified T cells with ConA or anti-CD3 mAb induced the same alterations.
In vitro, the downregulation of CD8β could be inhibited by the caspase inhibitor, z-VAD. These results suggest that the aberrant CTL phenotype found in the TIL
of glioma-bearing rats may be novel signals for their impending death and degenerating anti-tumor immune function.
Received: 27 February 2001 / Accepted: 26 April 2001 相似文献
19.
Immune responses to p53 in patients with cancer:enrichment in tetramer+ p53 peptide-specific T cells and regulatory T cells at tumor sites 总被引:2,自引:0,他引:2
Albers AE Ferris RL Kim GG Chikamatsu K DeLeo AB Whiteside TL 《Cancer immunology, immunotherapy : CII》2005,54(11):1072-1081
Objective: A majority of human cancers, including head and neck cancer (HNC), overexpress p53. Although T cells specific for wild-type (wt) sequence p53 peptides are detectable in the peripheral blood of patients with HNC, it is unknown whether such T cells accumulate in tumor-involved tissues. Also, the localization of regulatory T cells (Treg) to tumor sites in HNC has not been investigated to date. Methods: Tumor infiltrating lymphocytes (TIL), tumor-involved or non-involved lymph node lymphocytes (LNL) and peripheral blood mononuclear cells (PBMC) were obtained from 24 HLA-A2.1+ patients with HNC. Using tetramers and four-color flow cytometry, the frequency of Treg and CD3+CD8+ T cells specific for wt p53 epitopes as well as their functional attributes were determined. Results: The CD3+CD8+ tetramer+ cell frequency was significantly higher (P<0.001) in TIL than autologous PBMC as was the percentage of CD4+CD25+ T cells (P<0.003). TIL were enriched in FOXp3+, GITR+ and CTLA-4+ Treg. CD8+ TIL had low expression and produced little IFN- after ex vivo stimulation relative to autologous PBMC or PBMC from NC. Conclusions: Anti-wt p53 epitope-specific T cells and Treg preferentially localize to tumor sites in patients with HNC. However, despite enrichment in tumor peptide-specific T cells, the effector cell population (CD3+CD8+) in TIL or PBMC was unresponsive to activation in the tumor microenvironment enriched in Treg. 相似文献