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1.
Invariant or Type 1 NKT cells (iNKT cells) are a unique population of lymphocytes that share characteristics of T cells and
natural killer (NK) cells. Various studies have shown that positive costimulatory pathways such as the CD28 and CD40 pathways
can influence the expansion and cytokine production by iNKT cells. However, little is understood about the regulation of iNKT
cells by negative costimulatory pathways. Here, we show that in vivo activation with α-GalCer results in increased cytokine
production and expansion of iNKT cells in the absence of programmed cell death ligand-1 (PD-L1, B7-H1, and CD274). To study
whether PD-L1 deficiency on NKT cells would enhance antigen-specific T-cell responses, we utilized CD8+ OT-1 OVA transgenic T cells. α-GalCer enhanced the expansion and cytokine production of OT-1 CD8+ cells after adoptive transfer into wild-type recipients. However, this expansion was significantly enhanced when OT-1 CD8+ T cells were adoptively transferred into PD-L1−/− recipients. To extend these results to a tumor model, we used the B16 melanoma system. PD-L1−/− mice given dendritic cells loaded with antigen and α-GalCer had a significant reduction in tumor growth and this was associated
with increased trafficking of antigen-presenting cells and CD8+ T cells to the tumors. These data demonstrate that abrogating PDL1:PD-1 interactions during the activation of iNKT cells
amplifies an anti-tumor response when coupled with DC vaccination. 相似文献
2.
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
3.
Amos SM Pegram HJ Westwood JA John LB Devaud C Clarke CJ Restifo NP Smyth MJ Darcy PK Kershaw MH 《Cancer immunology, immunotherapy : CII》2011,60(5):671-683
Toll-like receptor (TLR) agonists can trigger broad inflammatory responses that elicit rapid innate immunity and promote the
activities of lymphocytes, which can potentially enhance adoptive immunotherapy in the tumor-bearing setting. In the present
study, we found that Polyinosinic:Polycytidylic Acid [Poly(I:C)] and CpG oligodeoxynucleotide 1826 [CpG], agonists for TLR
3 and 9, respectively, potently activated adoptively transferred T cells against a murine model of established melanoma. Intratumoral
injection of Poly(I:C) and CpG, combined with systemic transfer of activated pmel-1 T cells, specific for gp10025–33, led to enhanced survival and eradication of 9-day established subcutaneous B16F10 melanomas in a proportion of mice. A series
of survival studies in knockout mice supported a key mechanistic pathway, whereby TLR agonists acted via host cells to enhance
IFN-γ production by adoptively transferred T cells. IFN-γ, in turn, enhanced the immunogenicity of the B16F10 melanoma line,
leading to increased killing by adoptively transferred T cells. Thus, this combination approach counteracted tumor escape
from immunotherapy via downregulation of immunogenicity. In conclusion, TLR agonists may represent advanced adjuvants within
the setting of adoptive T-cell immunotherapy of cancer and hold promise as a safe means of enhancing this approach within
the clinic. 相似文献
4.
Hiroki Yamaue M.D. Hiroshi Tanimura Makoto Iwahashi Takuya Tsunoda Masaji Tani Masaya Inoue 《Biotherapy》1990,2(1):51-61
We had demonstrated that the NK cell mediated cytotoxicity of murine spleen cells could be augmented byin vivo priming and subsequentin vitro challenge with a streptococcal preparation OK432, and the cell surface phenotype of induced killer cells was Thy-1+, asialo GM1+, suggesting that the activated cells were of NK lineage (OK-NK cell). We had also clarified that IL-2 played a major role in inducing the OK-NK cells via the production of IFN-. In this study, we examined the effect of adoptive transfer of OK-NK cells on syngeneic tumors in mice. Mice were implanted with SP2 myeloma cells intraperitoneally (i.p.), or C26 colon adenocarcinoma cells subcutaneously to make the models of peritonitis carcinomatosa or solid tumor, and the OK-NK cells were transferred i.p. or intratumorally, adoptively. By the adoptive transfer of OK-NK cells, 92% of mice bearing SP2-tumor had be cured. The tumor growth of C26-solid tumor was inhibited, and the survival rate of mice bearing C26-tumor was significantly increased. The intratumoral remnants of125I-labelled OK-NK cells were 61, 27 and 8% at 4, 12 and 36h after intratumoral transfer, respectively. By multiple transfer of OK-NK cells, the antitumor effect was more effectively augmented than that of a single transfer. Results in this study suggested that OK-NK cells could be useful for the therapy of cancer patients. 相似文献
5.
Moustaki A Argyropoulos KV Baxevanis CN Papamichail M Perez SA 《Cancer immunology, immunotherapy : CII》2011,60(12):1683-1695
We have previously reported a synergistic effect between hydrocortisone (HC) and IL-15 on promoting natural killer (NK) cell
expansion and function. In the present study, we extend our findings to methylprednisolone (MeP) and dexamethasone (Dex),
thus ascribing to glucocorticoids (GCs) a general feature as positive regulators of IL-15-mediated effects on NK cells. We
demonstrate that each GC when combined with IL-15 in cultures of peripheral blood (PB)-derived CD56+ cells induces increased expansion of CD56+CD3− cells displaying high cytolytic activity, IFN-γ production potential and activating receptor expression, including NKp30,
NKp44, NKp46, 2B4, NKG2D and DNAM-1. Furthermore, GCs protected NK cells from IL-15-induced cell death. The combination of
IL-15 with GCs favored the expansion of a relatively more immature CD16low/neg NK cell population, with high expression of NKG2A and CD94, and significantly lower expression of KIR (CD158a and CD158b)
and CD57, compared to IL-15 alone. IL-15-expanded NK cells, in the presence or absence of GCs, did not express CD62L, CXCR1
or CCR7. However, the presence of GCs significantly increased the density of CXCR3 and induced strong CXCR4 expression on
the surface of NK cells. Our data indicate that IL-15/GC-expanded NK cells, apart from their increased proliferation rate,
retain their functional integrity and exhibit a migratory potential rendering them useful for adoptive transfer in NK cell-based
cancer immunotherapy. 相似文献
6.
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
7.
Salagianni M Lekka E Moustaki A Iliopoulou EG Baxevanis CN Papamichail M Perez SA 《Journal of immunology (Baltimore, Md. : 1950)》2011,186(6):3327-3335
Previous work from our laboratory showed that hydrocortisone (HC) combined with IL-15 induces expansion of activated human NK cells. We set up an experimental tumor model to evaluate the use of adoptively transferred, HC plus IL-15 (HC/IL-15)-activated and -expanded murine NK cells in the treatment of syngeneic mice carrying established lung metastases of the CT26 transplantable tumor. We also examined the effect of denileukin diftitox (Ontak) on the depletion of regulatory T cells to enhance the in vivo antitumor immunity induced by the adoptively transferred NK cells. Our results clearly demonstrate that murine DX5(+) NK cells are largely expanded in the presence of IL-15 plus HC while retaining intact their functional status. Moreover, when intravenously infused, they mediated significant antitumor responses against CT26 lung tumors in syngeneic BALB/c animals that were further enhanced upon pretreatment of the tumor-bearing animals with Ontak. Total splenocytes and isolated splenic T cells from NK-treated mice responded in vitro against CT26 tumor cells as evidenced by IFN-γ-based ELISPOT, proliferation, and cytotoxicity assays. Importantly, animals treated with Ontak plus adoptive transfer of HC/IL-15-expanded NK cells significantly retarded CT26 tumor growth after a rechallenge with the same tumor s.c. in their flanks. Taken altogether, our data suggest that NK cell adoptive transfer can trigger adaptive antitumor T cell responses, and regulatory T cell depletion by Ontak is mandatory for enabling HC/IL-15-activated NK cells to promote long-lasting adaptive antitumor immunity. 相似文献
8.
Nechushtan H Pham D Zhang Y Morgensztern D Yi KH Shin SU Federoff HJ Bowers WJ Tolba KA Rosenblatt JD 《Cancer immunology, immunotherapy : CII》2008,57(5):663-675
Treatment of cancer with cytotoxic agents may induce lymphopenia. Adoptively transferred T cells have been reported to display enhanced anti-tumor efficacy in the lymphopenic setting. We reasoned that the anti-tumor effects of adoptively transferred cells in the lymphopenic host could be further augmented through local provision of an innate stimulus in the tumor bed. Utilizing a model in which mice were irradiated to induce lymphopenia, with limited shielding to allow tumor growth, we demonstrate that “triple” therapy consisting of radiation-induced lymphopenia, adoptive transfer of naïve CD8+ T cells, and intra-tumoral HSV amplicon injection resulted in reduced tumor growth compared to the combination of any two of the aforementioned interventions. To gain insight into the mechanism underlying this effect we studied the effects of HSV amplicon transduction into tumors on cytokine expression and on anti-tumor specific T cells. HSV amplicon transduction specifically induced several cytokine mRNAs including IFN-γ, and IP-10. Adoptively transferred transgenic OT-1 T cells directed against Ovalbumin were more effective against Ovalbumin-expressing tumors when combined with intra-tumoral HSV amplicon injections in the lymphopenic host. Following intra-tumoral HSV-amplicon injections, anti-tumor T cells secreted higher levels of interferon-γ in response to in-vitro re-stimulation with tumor cells, implying that HSV amplicon injection provided a strong signal for T cell activation. Combining adoptive transfer of naïve T cells in the lymphopenic setting with local T cell stimulation may facilitate expansion and activation of anti-tumor T cell populations in vivo, resulting in enhanced anti-tumor responses without the need to resort to prolonged in vitro T cell culture and/or manipulation. 相似文献
9.
Akio Uemura Tetsuo Takehara Takuya Miyagi Takahiro Suzuki Tomohide Tatsumi Kazuyoshi Ohkawa Tatsuya Kanto Naoki Hiramatsu Norio Hayashi 《Cancer immunology, immunotherapy : CII》2010,59(3):453-463
Although the anti-tumor effect of IL-12 is mediated mostly by IFNγ, which cell types most efficiently produce IFNγ and therefore
initiate or promote the anti-tumor effect of IL-12 has not been clearly determined. In the present study, we demonstrated
hydrodynamic injection of the IL-12 gene led to prolonged IFNγ production, NK-cell activation and complete inhibition of liver
metastasis of CT-26 colon cancer cells in wild-type mice, but not in IFNγ knockout mice. NK cells expressed higher levels
of STAT4 and upon IL-12 administration displayed stronger STAT4 phosphorylation and IFNγ production than non-NK cells. Adoptive
transfer of wild-type NK cells into IFNγ knockout mice restored IL-12-induced IFNγ production, NK-cell activation and anti-tumor
effect, whereas transfer of the same number of wild-type non-NK cells did not. In conclusion, NK cells are predominant producers
of IFNγ that is critical for IL-12 anti-tumor therapy. 相似文献
10.
Effector cell functions are regulated by a number of positive signals for the mediation of antitumor immunity. The CD40 and
CD40 ligand (CD40L) interaction has been implicated in the generation of effective cell-mediated and humoral immune responses,
where cytokines have been shown to play a significant role in the expression of these molecules. Our earlier studies have
shown that spontaneous regression of a rat histiocytoma transplanted s.c. is mediated by CD8+ CD3− NK cells. The CD40-CD40L mediation during tumor regression was of interest. Tumor-transplanted animals showed enhanced expression
of CD40L on natural killer (NK) and T cells, when compared to cells from normal animals. CD40 expression on AK-5 tumor cells
was also induced after s.c. transplantation. Administration of anti-(interleukin-12) (anti-IL-12) and anti-(interferon γ)
(anti-IFNγ) antibodies in tumor-bearing animals showed down-regulation of the expression of CD40L on NK and T cells with simultaneous
inhibition of cytotoxic acitivity of NK cells, cytokine release and the production of antitumor antibody. Naive NK cells,
when co-cultured with fixed AK-5 cells, were induced to express CD40L. CD40L expression modulated the immune response exerted
by NK cells, in part by the activation of nuclear factor kB (NF-kB). Furthermore, the signaling via CD40L through the use
of anti-CD40L antibody promoted the in vitro activation of cytotoxic as well as NF-kB binding activity in NK cells from tumor-transplanted
animals. These observations demonstrate that the expression of CD40L by the effector cells is regulated by IL-12 and IFNγ,
and could effectively modulate the NK-cell-mediated immune response during the regression of AK-5 tumor.
Received: 1 June 2000 / Accepted: 27 July 2000 相似文献
11.
Yu Zhang Yair Eliav Seung-uon Shin Taylor H. Schreiber Eckhard R. Podack Tamar Tadmor Joseph D. Rosenblatt 《Cancer immunology, immunotherapy : CII》2013,62(1):87-99
The mechanisms by which B lymphocytes inhibit anti-tumor immunity remain poorly understood. Murine EMT-6 mammary tumors grow readily in immune competent mice (BALB/c), but poorly in B-cell-deficient μ?/? BALB/c mice (BCDM). T regulatory cell (Treg) expansion and function were impaired in BCDM compared with BALB/c. In this study, we compared tumor growth, Treg cell proliferation, tumor lymphocyte infiltration and cytolytic T cell activity in BALB/c, BCDM and BCDM partially reconstituted with B cells by adoptive transfer (BCDM+B). Partial reconstitution of BCDM with adoptively transferred B cells restored EMT-6 tumor growth, which was independent of IL-10 secretion by B cells. Instead, high frequencies of intratumoral B cells were associated with increased recruitment and proliferation of Treg cells within the tumor microenvironment. The B-cell-dependent accumulation of Treg within the tumor microenvironment was associated with reduced tumor infiltration by CD49+ NK and CD8+ T cells and reduced cytotoxic T cell activity against EMT-6 targets. Our studies indicate that tumor-dependent immunosuppression of T-cell-mediated anti-tumor immunity is coordinated within the tumor microenvironment by B-cell-dependent cross talk with Treg cells, which does not require production of IL-10 by B cells. 相似文献
12.
Carolina Berger Michael Berger Brian C. Beard Hans-Peter Kiem Theodore A. Gooley Stanley R. Riddell 《PloS one》2013,8(2)
The adoptive transfer of antigen-specific effector T cells is being used to treat human infections and malignancy. T cell persistence is a prerequisite for therapeutic efficacy, but reliably establishing a high-level and durable T cell response by transferring cultured CD8+ T cells remains challenging. Thus, strategies that promote a transferred high-level T cell response may improve the efficacy of T cell therapy. Lymphodepletion enhances persistence of transferred T cells in mice in part by reducing competition for IL-15, a common γ-chain cytokine that promotes T cell memory, but lymphodepleting regimens have toxicity. IL-15 can be safely administered and has minimal effects on CD4+ regulatory T cells at low doses, making it an attractive adjunct in adoptive T cell therapy. Here, we show in lymphoreplete macaca nemestrina, that proliferation of adoptively transferred central memory-derived CD8+ effector T (TCM/E) cells is enhanced in vivo by administering IL-15. TCM/E cells migrated to memory niches, persisted, and acquired both central memory and effector memory phenotypes regardless of the cytokine treatment. Unexpectedly, despite maintaining T cell proliferation, IL-15 did not augment the magnitude of the transferred T cell response in blood, bone marrow, or lymph nodes. T cells induced to proliferate by IL-15 displayed increased apoptosis demonstrating that enhanced cycling was balanced by cell death. These results suggest that homeostatic mechanisms that regulate T cell numbers may interfere with strategies to augment a high-level T cell response by adoptive transfer of CD8+ TCM/E cells in lymphoreplete hosts. 相似文献
13.
Koichiro Abe Mamoru Harada Koji Tamada Osamu Ito Tieli Li Kikuo Nomoto 《Cancer immunology, immunotherapy : CII》1997,45(5):225-233
Both natural killer (NK) cells and macrophages are thought to be the main effectors responsible for early antitumor defense.
In this study, we investigated the role of tumor-infiltrating NK cells in initiating nitric oxide (NO) production by tumor-associated
macrophages (TAM). The in vivo depletion of NK cells prior to the i.p. inoculation of melanoma cells resulted in a significant
decrease in the NO production of the TAM prepared from the peritoneal exudate cells (PEC). Such prior NK cell depletion also
decreased the ability of TAM to show any antitumor activity in vitro. The addition of N
G-monomethyl-L-arginine (Me-L-Arg) to the culture partially inhibited the ability of TAM to suppress the proliferation of melanoma cells and also decreased
their cytolytic activity against melanoma cells. These results suggest that the TAM exhibited both cytostatic and cytolytic
activities through their NO production. In an in vivo assay, the administration of Me-L-Arg permitted the more rapid growth of i.p. inoculated melanoma cells compared with the control. On the other hand, the decreased
NO production of TAM, resulting from the prior NK cell depletion, was restored by the i.p. administration of interferon γ
(IFNγ). In addition, the in vivo administration of anti-IFNγ mAb into mice inoculated i.p. with melanoma cells also significantly
decreased the NO production of TAM in peritoneal exudate cells. Furthermore, the tumor-infiltrating NK cells produced a considerable
level of IFNγ. Overall, these results indicate that early-appearing tumor-infiltrating NK cells play an important role in
the NO production of TAM through their IFNγ production.
Received: 11 March 1997 / Accepted: 31 July 1997 相似文献
14.
Sagan D Mörtl S Müller I Eckardt-Schupp F Eichholtz-Wirth H 《Apoptosis : an international journal on programmed cell death》2007,12(4):753-767
The molecular causes for enhanced radiosensitivity of Nijmegen Breakage Syndrome cells are unclear, especially as repair of DNA damage is hardly impeded in these cells. We clearly demonstrate that radiation
hypersensitivity is accompanied by enhanced γ-radiation-induced apoptosis in NBS1 deficient lymphoblastoid cell lines. Differences in the apoptotic behavior of NBS1
−/− and NBS1
+/− cells are not due to an altered p53 stabilization or phosphorylation in NBS1
−/− cells. γ-radiation-induced caspase-8 activity is increased and visualization of CD95 clustering by laser scanning microscopy
shows a significant higher activation of the death receptor in NBS1
−/− cells. Further investigation of the molecular mechanisms reveals a role for reactive oxygen species-triggered activation
of CD95. These results demonstrate that NBS1 suppresses the CD95 death receptor-dependent apoptotic pathway after γ-irradiation and evidence is given that this is achieved
by regulation of the PI3-K/AKT survival pathway. 相似文献
15.
Timothy L. Frankel William Burns John Riley Richard A. Morgan Jeremy L. Davis Kenichi Hanada Martha Quezado Steven A. Rosenberg Richard E. Royal 《Cancer immunology, immunotherapy : CII》2010,59(12):1757-1769
In a recent clinical trial, a patient exhibited regression of several pancreatic cancer metastases following the administration
of the immune modulator Ipilimumab (anti-CTLA-4 antibody). We sought to characterize the immune cells responsible for this
regression. Tumor infiltrating lymphocytes (TIL-2742) and an autologous tumor line (TC-2742) were expanded from a regressing
metastatic lesion excised from this patient. Natural killer (NK) cells predominated in the TIL (92% CD56+) with few T cells (12% CD3+). A majority (88%) of the NK cells were CD56brightCD16−. TIL-2742 secreted IFN-γ and GM-CSF following co-culture with TC-2742 and major histocompatibility complex mismatched pancreatic
tumor lines. After sorting TIL-2742, the purified CD56+CD16−CD3− subset showed reactivity similar to TIL-2742 while the CD56−CD16−CD3+ cells exhibited no tumor recognition. In co-culture assays, TIL-2742 and the NK subset expressed high reactivity to several
pancreatic and prostate cancer cell lines and could lyse the autologous tumor as well as pancreas and prostate cancer lines.
Reactivity was partially abrogated by blockade of TRAIL. We thus identified a unique subset of NK cells (CD56brightCD16dim) isolated from a regressing metastatic pancreatic cancer in a patient responding to Ipilimumab. This represents the first
report of CD56+CD16− NK cells with apparent specificity for pancreatic and prostate cancer cell lines and associated with tumor regression following
the treatment with an immune modulating agent. 相似文献
16.
Dowell AC Oldham KA Bhatt RI Lee SP Searle PF 《Cancer immunology, immunotherapy : CII》2012,61(5):615-628
4-1BB ligation co-stimulates T cell activation, and agonistic antibodies have entered clinical trials. Natural killer (NK)
cells also express 4-1BB following activation and are implicated in the anti-tumour efficacy of 4-1BB stimulation in mice;
however, the response of human NK cells to 4-1BB stimulation is not clearly defined. Stimulation of non-adherent PBMC with
OVCAR-3 cells expressing 4-1BB ligand (4-1BBL) or IL-12 resulted in preferential expansion of the NK cell population, while
the combination 4-1BBL + IL-12 was superior for the activation and proliferation of functional NK cells from healthy donors
and patients with renal cell or ovarian carcinoma, supporting long-term (21 day) NK cell proliferation. The expanded NK cells
are predominantly CD56bright, and we show that isolated CD56dimCD16+ NK cells can switch to a CD56brightCD16− phenotype and proliferate in response to 4-1BBL + IL-12. Whereas 4-1BB upregulation on NK cells in response to 4-1BBL required
‘help’ from other PBMC, it could be induced on isolated NK cells by IL-12, but only in the presence of target (OVCAR-3) cells.
Following primary stimulation with OVCAR-3 cells expressing 4-1BBL + IL-12 and subsequent resting until day 21, NK cells remained
predominantly CD56bright and retained both high cytotoxic capability against K562 targets and enhanced ability to produce IFNγ relative to NK cells
in PBMC. These data support the concept that NK cells could contribute to anti-tumour activity of 4-1BB agonists in humans
and suggest that combining 4-1BB-stimulation with IL-12 could be beneficial for ex vivo or in vivo expansion and activation
of NK cells for cancer immunotherapy. 相似文献
17.
Guenterberg KD Lesinski GB Mundy-Bosse BL Karpa VI Jaime-Ramirez AC Wei L Carson WE 《Cancer immunology, immunotherapy : CII》2011,60(9):1281-1288
Interferon-alpha (IFN-α) is an immunomodulatory cytokine that is used clinically for the treatment of melanoma in the adjuvant
setting. The cellular actions of IFN-α are regulated by the suppressors of cytokine signaling (SOCS) family of proteins. We
hypothesized that the anti-tumor activity of exogenous IFN-α would be enhanced in SOCS1-deficient mice. SOCS1-deficient (SOCS1−/−) or control (SOCS1+/+) mice on an IFN-γ−/− C57BL/6 background bearing intraperitoneal (i.p.) JB/MS murine melanoma cells were treated for 30 days with i.p. injections
of IFN-A/D or PBS (vehicle). Log-rank Kaplan-Meier survival curves were used to evaluate survival. Tumor-bearing control SOCS1+/+ mice receiving IFN-A/D had significantly enhanced survival versus PBS–treated mice (P = 0.0048). The anti-tumor effects of IFN-A/D therapy were significantly enhanced in tumor-bearing SOCS1−/− mice; 75% of these mice survived tumor challenge, whereas PBS-treated SOCS1−/− mice all died at 13-16 days (P = 0.00038). Antibody (Ab) depletion of CD8+ T cells abrogated the anti-tumor effects of IFN-A/D in SOCS1−/− mice as compared with mice receiving a control antibody (P = 0.0021). CD4+ T-cell depletion from SOCS1−/− mice also inhibited the effects of IFN-A/D (P = 0.0003). IFN-A/D did not alter expression of CD80 or CD86 on splenocytes of SOCS1+/+ or SOCS1−/− mice, or the proportion of T regulatory cells or myeloid-derived suppressor cells in SOCS1+/+ or SOCS1−/− mice. An analysis of T-cell function did reveal increased proliferation of SOCS1-deficient splenocytes at baseline and in
response to mitogenic stimuli. These data suggest that modulation of SOCS1 function in T-cell subsets could enhance the anti-tumor
effects of IFN-α in the setting of melanoma. 相似文献
18.
Liu Z Noh HS Chen J Kim JH Falo LD You Z 《Journal of immunology (Baltimore, Md. : 1950)》2008,181(6):4363-4370
Administration of anti-CD25 mAb before an aggressive murine breast tumor inoculation provoked effective antitumor immunity. Compared with CD4(+) T cells purified from anti-CD25 mAb-pretreated mice that did not reject tumor, CD4(+) T cells purified from anti-CD25 mAb-pretreated mice that rejected tumor stimulated by dendritic cells (DCs) produced more IFN-gamma and IL-2, and less IL-17 in vitro, and ignited protective antitumor immunity in vivo in an adoptive transfer model. Tumor Ag-loaded DCs activated naive CD8(+) T cells in the presence of these CD4(+) T cells in vitro. Tumor Ag and adoptively transferred CD4(+) T cells were both required for inducing a long-term tumor-specific IFN-gamma-producing cellular response and potent protective antitumor activity. Although adoptively transferred CD4(+) T cells ignited effective tumor-specific antitumor immunity in wild-type mice, they failed to do so in endogenous NK cell-depleted, Gr-1(+) cell-depleted, CD40(-/-), CD11c(+) DC-depleted, B cell(-/-), CD8(+) T cell-depleted, or IFN-gamma(-/-) mice. Collectively, the data suggest that adoptively transferred CD4(+) T cells orchestrate both endogenous innate and adaptive immunity to generate effective tumor-specific long-term protective antitumor immunity. The data also demonstrate the pivotal role of endogenous DCs in the tumor-specific protection ignited by adoptively transferred CD4(+) T cells. Thus, these findings highlight the importance of adoptively transferred CD4(+) T cells, as well as host immune components, in generating effective tumor-specific long-term antitumor activity. 相似文献
19.
Schrama D Voigt H Eggert AO Xiang R Reisfeld RA Becker JC 《Cancer immunology, immunotherapy : CII》2006,55(7):861-866
An effective immunological eradication of tumors by the adaptive immune system depends on T cell priming, expansion of specific
T cells and their effector function. It has been shown that either step may be impaired in the tumor-bearing host, and several
strategies have been used to improve antitumor immune responses. In this regard, tumor-targeted IL2 therapy leads to the destruction
of established melanoma metastases in fully immune competent mice as previously demonstrated. This effect has been attributed,
but never directly confirmed, to the boost of antigen-experienced T cells. To this end, we demonstrate the absence of any
antitumor effect of targeted IL2 in mice characterized by an impaired priming of T cell responses. Notably, in these animals
tumor-targeted IL2 therapy induced tumor regression only after adoptive transfer of tumor-conditioned splenocytes. A detailed
analysis revealed that T cells present within the transferred splenocytes were actively participating in the immune response
as these were clonally expanded after targeted IL2 therapy. In summary, we demonstrate here that in LTα−/− mice lacking sufficient numbers of tumor-specific T cells only the passive transfer of such cells prior to therapy restores
the efficacy of tumor-targeted IL2 therapy. Thus, the antitumor effect of tumor-targeted IL2 is indeed based on the boost
of pre-existing T cell responses. 相似文献
20.
The presence of a relatively mature CD4+ CD8− (SP) T cell subset in mouse thymus has been demonstrated. Composing of 10% of total CD4SP thymocytes, this subset is defined by the absence of 3G11 and 6C10 expression with a phenotype of CD69+/−, HSAmed/lo and heterogeneous for Qa-2 expression. The proliferation capability of TCRαβ+ 3Gl l− 6C10− CD4+ CD8− thymocytes was high while using Con A stimulus. And Con A stimulation could result in secretion of IL4, IL-10, IL-6 and a little amount of IFNγ. IL-2 was barely detectable. This is distinct from typical Th0 type cytokines. The cells of this subset were NK1.1 negative, but strongly expressed GATA-3 mRNA. The results suggest that the CD4+ subset of 3G11− 6C10− NK1.1− phenotype possesses immunocompetent cells with functions characteristic of Th2-like cytokines, which may indicate the cells at transitional status from Th0 to Th2, with a propensity to Th2. 相似文献