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1.
Effects of interleukin-12 on in vitro culture with interleukin-2 of regional lymph node lymphocytes from lung cancer patients 总被引:2,自引:0,他引:2
T. Hanagiri Mitsuhiro Takenoyama Takashi Yoshimatsu Chikashi Hirashima Ichiro Yoshino Kozo Nakanishi Akira Nagashima Kikuo Nomoto Kosei Yasumoto 《Cancer immunology, immunotherapy : CII》1996,43(2):87-93
In the present study, we carried out a functional analysis of regional lymph node lymphocytes (RLNL) from patients with lung
cancer after in vitro activation by interleukin-2 (IL-2) and interleukin-12 (IL-12). IL-12 (100 U/ml) enhanced both the proliferation
and cytotoxic activity of RLNL in a culture with low doses of IL-2 (5 – 10 JRU/ml). After comparing an RLNL culture with a
low dose of IL-2 alone, a higher proportion of CD8+ cells and CD56+ cells and a lower proportion of CD4+ cells were found in the culture with both IL-12 and a low dose of IL-2. Such a combination of the cytokines effectively activated
RLNL in terms of the expression of IL-2 receptors. In the culture condition of IL-12 and a low dose of IL-2, a synergistic
effect was observed in the production of such cytokines as interferon γ, tumor necrosis factor α (TNFα), and TNFβ, as well
as in tumor cytotoxicity. However, the addition of IL-12 inhibited the cytotoxicity of RLNL in the culture with a high dose
of IL-2 (100 JRU/ml). This inhibition is considered to be partially due to the endogenous production of TNFα by lymphocytes,
because the neutralization of TNFα bioactivity partially restored the cytotoxic activities of RLNL. Furthermore, in the presence
of hydrocortisone, IL-12 synergistically enhanced the cytotoxic activity of RLNL cultured with a high dose of IL-2. These
results provide useful information about the improvement of adoptive immunotherapy against cancer using RLNL.
Received: 2 February 1996 / Accepted: 30 July 1996 相似文献
2.
Takami Sato 《Cancer immunology, immunotherapy : CII》1996,43(3):174-179
We have developed a novel approach to cancer immunotherapy – an autologous whole-cell vaccine modified with the hapten dinitrophenyl
(DNP). This approach elicits significant inflammatory responses in metastatic sites and some objective tumor responses. Post-surgical
adjuvant immunotherapy with DNP-modified melanoma vaccine in a setting of micrometastatic disease produces significant survival
prolongation in stage III melanoma patients. Histologically, the inflammatory responses of the tumor consist of infiltration
by lymphocytes, the majority of which are CD8+, HLA-DR+ T cells. T cells from these lesions tend to have mRNA for interferon γ. T cell receptor analysis suggests that the tumor-infiltrating
T cells are clonally expanded. DNP-modified vaccine also induces T cells in the peripheral blood, which respond to DNP-modified
autologous cells in a hapten-specific, MHC-restricted manner. Moreover, a T cell line generated from these lymphocytes responded
to only a single HPLC fraction of MHC-associated, DNP-modified tumor peptides. Since inflammatory responses in metastases
were not consistently associated with dramatic tumor regression, we considered the possibility of immunosuppression at the
tumor site. We found that mRNA for the anti-inflammatory cytokine, interleukin-10 (IL-10) is expressed in most metastatic
melanoma tissues and subsequently demonstrated that IL-10 protein is produced by melanoma cells. Thus the efficacy of DNP
vaccine could be further enhanced by inhibition of IL-10 production or binding. Finally, we expect these results obtained
with melanoma to be applicable to other human cancers.
Received: 6 August 1996 / Accepted: 20 September 1996 相似文献
3.
N. Tsavaris C. Baxevanis P. Kosmidis M. Papamichael 《Cancer immunology, immunotherapy : CII》1996,43(2):94-102
In the present study we evaluated the response rate and the immunorestorative properties of interferon α2b (IFnα2b) administered
to patients with advanced renal cell carcinoma (RCC), melanoma (MEL) or colorectal cancer (CC). We studied the immune status
and correlated it with clinical responses. Thirty-five patients with advanced RCC, and 14 with MEL were treated with recombinant
INFα2b. The dose was increased progressively from 5×106 IU/day in the first week (three times every week) to 10×106 IU/day in the second week and thereafter to 15×106 IU/day subcutaneously. In patients with CC INFα2b was given at 5×106 IU/day every other day (three times every week); these patients also received (together with INF) leucovorin 200 mg m–2 day–1 in a 1-h i. v. infusion every week, and mid-infusion 400 mg/m2 5-FU was administered as an intravenous bolus every week. The response rate was as follows: for RCC, 6 patients achieved
partial response (PR), 10 stable disease (SD), and 21 progressed (PD); for MEL, 5 patients achieved PR and 9 PD; for CC, 6
achieved PR, 5 SD, and 9 PD. In all patients blood was withdrawn prior to INFα2b treatment and then monthly. T lymphocytes,
after isolation from peripheral blood, were tested for proliferation in the autologous mixed-lymphocyte reaction and allogeneic
mixed-lymphocyte reaction, interleukin-2 (IL-2) production, expression of IL-2 receptors during the allogeneic-mixed-lymphocyte
reaction, and the production of IL-1 by peripheral blood monocytes. Striking increases were demonstrated in all parameters
2 months after treatment with INFα2b. In comparison to normal controls, all patients with the malignant neoplasms presented
decreased (>45%) mean values of the immunological parameters under investigation (P 0.0001). Responders (patients with RCC, MEL, and PR) presented lower mean values of all the parameters studied than did non-responders
(P 0.0001). Patients with CC presented the lowest mean values of the parameters than did the other patients (RCC, MEL) (P 0.0001). After therapy with INFα2b, patients with RCC experiencing PR showed a mean increase of more than 30% (P 0.0001). Patients with SD showed a mean increase of about 20% (P 0.0001), and those with PD showed a 6% increase in the immunological parameters under investigation. Patients with MEL experiencing
PR showed a mean increase of more than 30% and patients with PD a decrease of more than 10% (P 0.0001). All patients, regardless of the clinical response, achieved an increase of more than 60% (P 0.0001). Administration of IFNα2b resulted in a marked potentiation of a deficient cellular immune response in vitro in those
patients with RCC and MEL who responded to the treatment. On the other hand, non-responders demonstrated a decrease in the
examined parameters and, in some, deterioration of the already depressed immunological functions was observed. This observation
can have prognostic significance regarding clinical response of INF. In contrast, our findings show that the immune stimulation
associated with INFα treatment in all our CC patients did not predict an improved clinical outcome. There are several theoretical
explanations for this discrepancy.
Received: 30 November 1996 / Accepted: 25 June 1996 相似文献
4.
Diverse manifestations of tumorigenicity and immunogenicity displayed by the poorly immunogenic B16-BL6 melanoma transduced with cytokine genes 总被引:4,自引:0,他引:4
Marjorie J. Arca John C. Krauss Scott E. Strome Mark J. Cameron A. E. Chang 《Cancer immunology, immunotherapy : CII》1996,42(4):237-245
We evaluated the in vivo response to the poorly immunogenic B16-BL6 (BL6) murine melanoma genetically altered to secrete
interleukin-2 (IL-2), IL-4, interferon γ (IFNγ) and granulocyte/macrophage-colony-stimulating factor (GM-CSF). Three parameters
were evaluated: (1) tumorigenicity, (2) vaccination of naive animals, and (3) assessment of antitumor reactivity of T cells
derived from tumor-draining lymph nodes (TDLN). Secretion of IL-2 abrogated the tumorigenicity of BL6, while IFNγ and IL-4
partially reduced tumorigenicity, and GM-CSF had no effect. Protective immunity to wild-type tumor challenge could not be
achieved by vaccination with irradiated cytokine-secreting tumors, although IL-2 and IL-4 secretion appeared to retard the
growth of the challenge inoculum significantly. An alternative method to evaluate the immunogenicity of the cytokine-secreting
tumors was to measure the ability of T cells obtained from TDLN to mediate regression of wild-type tumor in adoptive immunotherapy.
Neither IL-2 nor IFNγ secretion resulted in the induction of immune T cells. By contrast, GM-CSF and IL-4 secretion were found
to induce immune T cells in the TDLN with GM-CSF being superior to IL-4. The combined secretion of GM-CSF and IL-4 did not
lead to enhanced induction of immune T cells. GM-CSF secretion was found to up-regulate B7-1 expression in TDLN, consistent
with an increase in the population of antigen-presenting cells. These studies demonstrated that reduced tumorigenicity by
cytokine secretion did not correlate with increased immunogenicity. With the cytokines examined, there was limited capability
of developing protective immunity against the BL6 tumor. Nevertheless, GM-CSF and IL-4 secretion significantly enhanced T
cell immune reactivity to the poorly immunogenic BL6 tumor.
Received: 30 January 1996 / Accepted: 22 March 1996 相似文献
5.
M. Margaret Prechel Yvonne Lozano Mark A. Wright J. Ihm M. R. I. Young 《Cancer immunology, immunotherapy : CII》1996,42(4):213-220
Lewis lung carcinoma (LLC-LN7) tumors stimulate myelopoiesis and increase the presence of granulocyte/macrophage (GM) progenitor
cells having natural suppressor activity. Treatment of these tumor-bearing mice with interleukin-12 (IL-12) resulted in minimal
immune modulation. The objective of this study was to determine whether eliminating natural suppressor activity would allow
for immune stimulation by IL-12. Treatment of LLC-LN7 tumor-bearing mice with vitamin D3 eliminated natural suppressor activity. In mice that were first treated with vitamin D3 and then also with IL-12, there was stimulation of splenic T cell proliferation in response to immobilized anti-CD3 plus
IL-2. In addition, spleen and lymph node cells from vitamin-D3/IL-12-treated tumor-bearing mice became stimulated in response to autologous tumor to produce interferon γ (IFNγ), although
IL-2 production was not stimulated. A prominent effect of the combined vitamin-D3/IL-12 treatment regimen was the synergistic augmentation of autologous tumor-specific cytolytic activity within the regional
lymph nodes. The generation of these tumor-specific effector cells required the presence of the tumor mass since such activity
was not elicited in the lymph nodes of mice from which the tumors had been surgically excised. The results of this study show
that, after treatment of tumor bearers with vitamin D3 to eliminate GM-suppressor cells, IL-12 can induce select regional antitumor immune responses, particularly IFNγ production
and cytolysis by regional lymph node cells of autologous tumor.
Received: 15 December 1995 / Accepted: 22 March 1996 相似文献
6.
Y. Kikuchi Eiji Imaizumi Yoshitaka Kataoka Junko Hirata Tsunekazu Kita Takehiko Tode Ichiro Nagata 《Cancer immunology, immunotherapy : CII》1997,43(5):257-261
The aim of this study was to elucidate the effect of intraperitoneal (i.p.) instillations of granulocyte-colony-stimulating
factor (G-CSF) and/or interleukin-2 (IL-2) on ascites formation and the survival time of nude mice with malignant ascites,
produced by i.p. inoculation of human ovarian cancer cells. When the nude mice were treated with medium alone, ascites was
observed in all mice 28 days after tumor inoculation. When the mice were treated with cis-diamminedichloroplatinum(II) (cisplatin) alone, G-CSF alone or IL-2 alone, it took 35 days for the ascites to form in all
mice. When cisplatin was combined with G-CSF or IL-2, one of ten mice did not form ascites during the observation period.
Surprisingly, when G-CSF and IL-2 were simultaneously administered, ascites formation was not observed in any mice. Although
i.p. treatment with cisplatin alone significantly prolonged the survival time, compared to medium alone, the lytic activity
of spleen cells against HRA cells was significantly suppressed. When G-CSF or IL-2 was combined with cisplatin, the suppression
by cisplatin was eliminated and subsequently resulted in a prolongation of the survival time. When G-CSF was combined with
IL-2, both the peritoneal and splenic macrophages/monocytes were stimulated and the splenic lytic activity was about double
that following treatment with G-CSF alone on IL-2 alone, suggesting that complete inhibition of ascites formation results
not only from a significant increase of the peritoneal macrophages but also from enhancement of the lytic activity. Two mice,
died from dissemination of tumor in the abdominal cavity, but eight mice survived without tumor for more than 90 days. As
confirmed by monitoring body weight and hematocrit, G-CSF and IL-2 seemed to have no adverse effect. From these results, we
conclude that a combination therapy with G-CSF and IL-2 might be of clinical use for inhibiting large amounts of ascites,
which may inhibit therapeutic effects for ovarian cancer patients.
Received: 20 May 1996 / Accepted: 19 September 1996 相似文献
7.
Keping Xie Suyun Huang Yunfang Wang Pedro J. Beltran Shin-Hun Juang Zhongyun Dong John C. Reed Timothy J. McDonnell David J. McConkey I. J. Fidler 《Cancer immunology, immunotherapy : CII》1996,43(2):109-115
Cytokine-mediated cell death in tumor cells can be achieved through endogenous nitric oxide (NO) from within tumor cells
or exogenous NO from either activated macrophages or endothelial cells. The purpose of this study was to determine the role
of Bcl-2 in NO-mediated apoptosis. The incubation of murine L929 and NIH3T3 cells with interleukin-1α (IL-1α) and interferon
γ (IFNγ) induced high endogenous NO production only in the L929 cells that also underwent apoptosis. NIH3T3 cells were not
resistant to NO-mediated apoptosis. In fact, the incubation of L929 and NIH3T3 cells with exogenous NO derived from NO donors,
sodium nitroprusside, or S-nitroso-N-acetyl-DL-penicillamine (SNAP) induced death, characterized by typical apoptotic morphology and DNA fragmentation, in both cell types,
but to a higher degree in NIH3T3 cells than in the L929 cells. We then measured the effect of Bcl-2 expression on exogenous
NO-induced apoptosis. At both the mRNA and protein levels, L929 fibroblasts expressed higher levels of endogenous mouse Bcl-2
than did NIH3T3 cells. At the same time, L929 cells were much more resistant to exogenous NO-induced cell death than were
NIH3T3 cells. The inverse correlation between mouse Bcl-2 expression and sensitivity to exogenous NO-mediated cell death was
also found in the murine K-1735 melanoma C-23 and X-21 clonal populations. Transfection of both NIH3T3 cells and L929 cells
with the human bcl-2 gene led to resistance to both exogenous and endogenous NO-mediated apoptosis. These data demonstrate that NO-mediated apoptosis
can be suppressed by expression of Bcl-2, suggesting that abnormal expression of Bcl-2 may influence the efficacy of tumor
immunotherapy.
Received: 28 June 1998 / Accepted: 23 August 1996 相似文献
8.
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
9.
We have investigated the effect of interleukin-2 (IL-2) secretion by KHT sarcoma cells upon their vaccine potential in syngeneic
C3Hf/He mice. Parental KHT tumor cells were transfected with the plasmid pBCMG-neo-mIL-2 to obtain a transfectant KHT-2-3-7
that secreted 20 units IL-2. KHT-2-3-7 cells elicited protective immunity in only 10% of the immunized mice, compared with
40% of mice immunized with irradiated parental KHT tumor colls. To minimize the contribution of potential antigenic differences
between the KHT-2-3-7 transfectant and parental KHT cells, a clone of KHT cells (KHT-C21) was isolated and used in subsequent
experiments. A number of transfectants secreting various amounts of IL-2, ranging from 2 units to 200 units, were obtained
following transfection of KHT-C21 cells with plasmid pBCMG-neo-mIL-2. Two of the transfectants, C21-13-4 and C21-1, each secreting
200 units IL-2, elicited protective immunity in a significantly lower fraction of mice than did irradiated KHT-C21 parental
tumor cells (P<0.0l). Two other transfectants C21-10 and C21-11, secreting 2 and 23 units IL-2 respectively, also showed lower vaccine potential
compared with the parental KHT-C21 clone (P<0.05). To minimize further any role for potential antigenic or other molecular differences between the individual transfectants
and the clonal KHT-C21 parental cells in lowering their vaccine efficacy, mice were immunized with a mixture of five transfectants,
and the results again showed significantly lower vaccine efficacy of the mixture compared with the irradiated parental C21
cells (P<0.0l). In view of published studies showing enhanced or unchanged efficacy of IL-2-secreting tumor cell vaccines, our observation
of the lower vaccine potential of IL-2-transduced tumor cells indicates that the vaccine efficacy of IL-2-secreting tumor
cells depends on the individual tumor. Such variability/unpredictability would hamper the clinical use of IL-2-secreting tumor
cells as vaccines.
Received: 23 April 1996 / Accepted: 7 February 1997 相似文献
10.
Schmidinger M Steger GG Wenzel C Locker GJ Brodowicz T Budinsky AC Wiltschke C Kramer G Marberger M Zielinski CC 《Cancer immunology, immunotherapy : CII》2000,49(7):395-400
Background: Because of the known efficacy of several cytokines in the treatment of advanced renal cell cancer (RCC), we have conducted
a phase II trial of the efficacy and toxicity of subcutaneous interferon γ (IFNγ) and interleukin-2 (IL-2). Methods: 63 patients with progressive metastatic RCC were treated with 100 μg recombinant IFNγ1b administered three times weekly during
weeks 1 and 2 and with 4.5 MU recombinant IL-2 administered on 4 consecutive days during weeks 3 and 4, every 6 weeks. Results: 11% of patients had an objective response (CR: 3%, PR: 8%), 33% had SD. Toxicity was generally mild. The median duration
of remissions (CR + PR) was 9.6 months; the median duration of SD 8 months. A significant survival benefit was evident at
a median observation time of 51 months for patients (44%) responding to therapy (P < 0.0001). Conclusions: we conclude that sequential treatment with IFNγ and IL-2 may prolong survival in patients with metastatic RCC responding
to therapy.
Received: 2 April 2000 / Accepted: 21 April 2000 相似文献
11.
Ugurel S Schrama D Keller G Schadendorf D Bröcker EB Houben R Zapatka M Fink W Kaufman HL Becker JC 《Cancer immunology, immunotherapy : CII》2008,57(5):685-691
Purpose Chemokines influence both tumor progression and anti-tumor immune response. A 32-bp-deletion polymorphism in the chemokine
receptor 5 gene (CCR5Δ32) has been shown to result in a non-functional protein. This study was aimed at evaluating the potential
impact of this gene polymorphism on disease progression and treatment outcome in patients with melanoma.
Patients and methods CCR5 genotyping was performed by PCR on DNA extracted from serum samples of 782 cutaneous melanoma patients with known disease
history and long-term clinical follow-up. Genotypes were correlated with patient survival and types of treatment.
Results Of 782 melanoma patients, 90 (11.5%) were heterozygous and 12 (1.5%) were homozygous for CCR5Δ32. Analyzing the complete cohort,
the disease-specific survival from date of primary diagnosis was not influenced by CCR5 status. Similarly, no significant
impact could be detected on the treatment outcome of stage III patients. In 139 stage IV patients receiving immunotherapy,
CCR5Δ32 was associated with a decreased survival compared to patients not carrying the deletion (median 12.5 vs. 20.3 months,
P = 0.029). Multivariate analysis revealed the CCR5 genotype as an independent factor impacting disease-specific survival in
this patient population (P = 0.002), followed by gender (P = 0.019) and pathological classification of the primary (pT; P = 0.022).
Conclusion The presence of the CCR5Δ32 polymorphism in patients with stage IV melanoma results in a decreased survival following immunotherapy
and may help to select patients less likely to benefit from this type of treatment.
Selma Ugurel and David Schrama have contributed equally to this work. 相似文献
12.
13.
Safety profile and anti-tumor effects of adoptive immunotherapy using gamma-delta T cells against advanced renal cell carcinoma: a pilot study 总被引:3,自引:0,他引:3
Kobayashi H Tanaka Y Yagi J Osaka Y Nakazawa H Uchiyama T Minato N Toma H 《Cancer immunology, immunotherapy : CII》2007,56(4):469-476
Purpose Although various types of immunotherapy have been used to improve the prognosis of patients with advanced renal cell carcinoma
(RCC), adoptive immunotherapy using gamma-delta (γδ) T cells has not yet been tried. In this study, we designed a pilot study
of adoptive immunotherapy using in vitro activated γδ T cells against advanced RCC to evaluate the safety profile and possible
anti-tumor effects of this study.
Experimental design Patients with advanced RCC after radical nephrectomy were administered via intravenous infusion in vitro-activated autologous
γδ T cells every week or every 2 weeks, 6–12 times, with 70 JRU of teceleukin. Adverse events, anti-tumor effects and immunomonitoring
were assessed. The anti-tumor effects were evaluated according to tumor doubling time (DT) by computed tomography (CT) and
immunomonitoring was performed by flow cytometric analysis.
Results Seven advanced RCC patients were entered in this study. The most common adverse events were fever, general fatigue and elevation
of hepatobiliary enzymes, but no severe adverse events were seen. Prolongation of tumor DT was seen in three out of five patients;
these three patients showed an increase in the number of γδ T cells in peripheral blood and also a high response to the antigen
in vitro.
Conclusions The results indicated that adoptive immunotherapy using in vitro-activated autologous γδ T cells was well tolerated and induced
anti-tumor effects. 相似文献
14.
Oriane Viale P. van der Bruggen Eva Meuer Regina Kunzmann Hubertus Kohler Roland Mertelsmann T. Boon Paul Fisch 《Immunogenetics》1996,45(1):27-34
Daudi Burkitt’s lymphoma cells, unlike other tumor cell lines, stimulate human T cells coexpressing the variable (V) region genes TCRG-V9 and V TCRD-V2 to proliferate and secrete lymphokines. Hybrids, derived by the fusion of Daudi cells with the human melanoma cell line MZ2-MEL
2.2, retain the morphology of melanoma cells. Unlike the parental melanoma cell line, these Daudi × MZ2-MEL 2.2 hybrids stimulate
secretion of tumor necrosis factor (TNF) and granulocyte/macrophage colony stimulating factor (GM-CSF) by CD4-positive Vγ9/Vδ2
T-cell clones. Whereas the stimulator phenotype of Daudi cells behaves as a dominant trait in Daudi × melanoma hybrids, the
expression of B-cell differentiation markers is suppressed. Thus, the γ/δ T-cell ligand expressed by Daudi cells behaves as
a dominant tumor antigen in Daudi × melanoma hybrids and is unrelated to the differentiated B-cell phenotype. Dominant expression
of the Daudi ligand for human Vγ9/Vδ2 T cells in these hybrids may provide a basis for defining the stimulatory principle
at the molecular level.
Received: 2 May 1996 / Revised: 15 July 1996 相似文献
15.
Matteo Santoni Francesco Massari Consuelo Amantini Massimo Nabissi Francesca Maines Luciano Burattini Rossana Berardi Giorgio Santoni Rodolfo Montironi Giampaolo Tortora Stefano Cascinu 《Cancer immunology, immunotherapy : CII》2013,62(12):1757-1768
Tumor-associated macrophages (TAMs) derived from peripheral blood monocytes recruited into the renal cell carcinoma (RCC) microenvironment. In response to inflammatory stimuli, macrophages undergo M1 (classical) or M2 (alternative) activation. M1 cells produce high levels of inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-12, IL-23 and IL-6, while M2 cells produce anti-inflammatory cytokines, such as IL-10, thus contributing to RCC-related immune dysfunction. The presence of extensive TAM infiltration in RCC microenvironment contributes to cancer progression and metastasis by stimulating angiogenesis, tumor growth, and cellular migration and invasion. Moreover, TAMs are involved in epithelial–mesenchymal transition of RCC cancer cells and in the development of tumor resistance to targeted agents. Interestingly, macrophage autophagy seems to play an important role in RCC. Based on this scenario, TAMs represent a promising and effective target for cancer therapy in RCC. Several strategies have been proposed to suppress TAM recruitment, to deplete their number, to switch M2 TAMs into antitumor M1 phenotype and to inhibit TAM-associated molecules. In this review, we summarize current data on the essential role of TAMs in RCC angiogenesis, invasion, impaired anti-tumor immune response and development of drug resistance, thus describing the emerging TAM-centered therapies for RCC patients. 相似文献
16.
17.
Cellular characteristics of peripheral blood lymphocytes and tumour-infiltrating lymphocytes in patients with gynaecological tumours 总被引:3,自引:0,他引:3
T. Schöndorf Heike Engel Carsten Lindemann Hannelore Kolhagen Alexander A. von Rücker Peter Mallmann 《Cancer immunology, immunotherapy : CII》1997,44(2):88-96
Immunotherapy of gynaecological cancer with tumour-infiltrating lymphocytes (TIL) or peripheral blood lymphocytes (PBL) has
become a valid treatment modality with varying degrees of success in obtaining an antitumour response. TIL consist of lymphocytes,
mainly T cells and minor populations of natural killer cells or B cells. Conventional cytogenetic studies of tumour cells
from patients with breast and ovarian cancer have shown multiple chromosomal abnormalities including chromosomes 7 and 12.
This study was designed to analyse the surface further, as well as investigate the intracellular, characteristics of TIL by
multicolour flow cytometry and the cytogenetic features by fluorescence in situ hybridization. Tumour cell, peripheral blood
and TIL samples from 25 patients (15 ovarian tumours, 8 breast cancers, 1 uterine sarcoma, 1 cervical carcinoma) were analysed
for their phenotype, the expression of major cytokines [interleukin-2 (IL-2), IL-4 and interferon γ (IFNγ)], their proliferation
rate, their cytotoxic ability and for the presence of numerical aberrations of chromosomes 7 and 12. All the tumour cells
showed a high frequency of numerical aberration in chromosomes 7 and 12, especially trisomies or tetrasomies and combined
aberrations. Trisomies of both chromosomes also occured at a low percentage in TIL and PBL.
Received: 20 June 1996 / Accepted: 4 January 1997 相似文献
18.
Nathalie Jacobs Alessandra Mazzoni Delia Mezzanzanica Donatella R. M. Negri Olga Valota Maria I. Colnaghi Michel P. Moutschen Jacques Boniver Silvana Canevari 《Cancer immunology, immunotherapy : CII》1997,44(5):257-264
T cell triggering can be achieved by monoclonal antibodies (mAbs) specific for the CD3/TcR complex. In the presence of appropriate
costimulation and/or progression factors, such triggering permits the generation of effector cells for immunotherapy protocols
involving the redirection of T cell lysis against tumor cells by mAbs bispecific for anti-CD3/anti-tumor cells (bs-mAbs).
Focusing our analysis on the clinically relevant bs-mAb OC/TR, we found that bs-mAbs generated with the same anti tumor specificity,
but two other anti-CD3 mAbs, TR66 and OKT3, have the same and a significantly lower lytic potential, respectively, compared
with that of OC/TR. To evaluate the relevance of the anti-CD3 component, we examined several anti-CD3 mAbs with respect to
binding parameters and the ability to trigger T lymphocytes. Competitive binding assays suggested that all anti-CD3 mAbs recognized
the same or overlapping epitopes, although mAbs BMA030 and OC/TR bound with lower avidity than did αCD3 (the bivalent anti-CD3
mAb produced by the hybrid hybridoma OC/TR), TR66 and OKT3, as determined by measurement of the affinity constants. In all
lymphocyte populations examined, which included resting peripheral blood mononuclear cells (PBMC), activated PBMC and T cell
clones, OKT3, BMA033 and OC/TR failed to mobilize Ca2+ without cross-linking, whereas αCD3, in both murine and murine-human chimeric versions, TR66 and BMA030, did not require
cross-linking. The ability to induce CD3 modulation was associated in part with the induction of Ca2+ fluxes. Despite the differences in the behavior of these mAbs in triggering the events that precede proliferation, all of
them ultimately led to expression of the IL-2 receptor and to proliferation in T cells in the presence of accessory cells.
Our data suggest that anti-CD3 mAbs that bind more rapidly (strong Ca2+ mobilizers) and more tightly under physiological conditions are good candidates for retargeting T cells in the bs-mAb clinical
application.
Received: 2 January 1997 / Accepted: 6 February 1997 相似文献
19.
Ursula Elsässer-Beile Ulrich Wetterauer Wolfgang Schultze-Seemann Harald Gallati Jürgen Schulte Mönting Sabine von Kleist 《Cancer immunology, immunotherapy : CII》1996,42(2):93-98
The immunological properties of tumor-infiltrating (TIL) and peripheral blood lymphocytes (PBL) from 29 patients with renal
cell carcinomas were characterized with respect to their phenotypic expression and cytokine production. TIL were isolated
from mechanically disaggregated tumor material and PBL from peripheral blood by gradient centrifugation. To eliminate all
non-lymphoid cells, CD3-positive cells were specifically separated from these cell fractions with anti-CD3 magnetic beads.
These pure CD3-positive PBL (CD3+PBL) and TIL (CD3+TIL) were cultured with pokeweed mitogen and the levels of the cytokines interleukin-1α (IL-1α), IL-1β, IL-2, interferon γ
(IFNγ), and tumor necrosis factor α (TNFα) measured in the 4-day post-inductional cell culture supernatants. In all cell cultures
a wide range of cytokine values was found, indicating a large variation in the immunological activity of the lymphocytes of
each individual. When the cell cultures of the CD3+TIL and CD3+PBL were compared in each patient similar values for IL-1α, IL-1β, IFNγ and TNFα were found. However CD3+TIL produced significantly lower levels of IL-2 than CD3+PBL upon mitogenic stimulation. This may be due to a lower CD4/CD8 ratio in the CD3+TIL as compared to the CD3+PBL. These results suggest that there are no fundamental qualitative and quantitative differences in the lymphokine-producing
capacity of CD3+TIL and CD3+PBL derived from patients with renal cell carcinomas.
Received: 8 August 1995 / Accepted: 23 January 1996 相似文献
20.
N. Jacobs Roland Greimers Alessandra Mazzoni Mohamed Trebak Nicole Schaaf-Lafontaine Jacques Boniver Michel P. Moutschen 《Cancer immunology, immunotherapy : CII》1996,42(6):369-375
In this study we have specifically investigated the participation of T cells in the cytotoxic activity of peripheral blood
lymphocytes (PBL) activated by interleukin-2 (IL-2, 50 U/ml) alone or in combination with an anti-CD3 mAb (BMA030, 10 ng/ml,
IgG2a). Purified CD3+ T cells, incubated in the presence of the anti-CD3 mAb for 4 days, mediated a cytotoxic activity against HL60 and U937 tumor
cell lines. Several findings suggested the involvement of a redirected-cytotoxicity phenomenon, since the lytic process was
restricted to target cell lines bearing the high-affinity Fcγ receptor (FcγRI) and T lymphocytes stimulated by IL-2 alone
did not lyse these cell lines. Furthermore, anti-CD3 mAb F(ab′)2, anti-CD3 IgG1 (UCHT1), phytohemagglutinin or staphylococcal enterotoxin A did not induce a similar cytotoxic activity in
T lymphocytes. The cytotoxic process occurred in the presence of a very low level of anti-CD3 antibodies (in the nanomolar
range). The cytotoxic activity of T cells stimulated by IL-2 or by IL-2 + BMA030, against OVCAR-3 cells (MOv18+ ovarian tumor cell line), was also compared in the presence of a bispecific antibody (OC/TR, anti-CD3 × MOv18). The stimulation
by IL-2 + BMA030 induced approximately a twofold higher cytotoxic activity than IL-2-activated T cells. This could be related
to the state of activation of effector cells stimulated by IL-2 + BMA030, since the phenotypic analysis showed an increased
proportion of T cells expressing several activation/differentiation markers (CD25, HLA-DR, CD45R0, adhesion molecules). These
findings could be applied to the design of therapeutic protocols using anti-CD3 ×antitumoral bispecific antibodies.
Received: 6 December 1995 / Accepted: 4 June 1996 相似文献