Publications by authors named "Abdel-Aziz A Zidan"

14 Publications

  • Page 1 of 1

Predictive value of immunological markers after bacille Calmette-Guérin induction in bladder cancer.

BJU Int 2021 Aug 27. Epub 2021 Aug 27.

Urology and Nephrology Center, Mansoura University, Mansoura, Egypt.

Objectives: To investigate the predictive value of different immunological markers on treatment outcomes after bacille Calmette-Guérin (BCG) induction in high-risk non-muscle-invasive bladder cancer (NMIBC).

Patients And Methods: Patients who underwent transurethral resection of bladder tumour for NMIBC were assessed for study eligibility. Urine and blood samples were taken from patients at baseline (immediately before first dose of induction) and after induction (4 h after last [sixth] dose). Urine samples were evaluated for interleukin (IL)-2 and IL-10 by solid-phase enzyme-linked immunosorbent assay. Blood samples were evaluated for tumour necrosis factor α (TNF-α), cytotoxic T-lymphocyte antigen 4 (CTLA-4) and transcription factors (TFs) (GATA-binding protein 3 [GATA3], T-box expressed in T cells [T-bet], and forkhead box protein 3 [FoxP3]) using quantitative reverse transcriptase-polymerase chain reaction analysis. Change pattern and fold change of each evaluable marker was assessed in relation to different treatment outcomes (initial complete response [ICR]/recurrence/progression).

Results: Between July 2013 and May 2019, 204 patients were included. Among evaluable markers, urinary IL-2 and serum TNF-α increased in all patients, serum CTLA-4 and FoxP3 showed a predominant decreased pattern in 188 (92.2%) and 192 (94.1%) patients, respectively. An ICR was achieved in 186 (91.2%) patients. Serum TNF-α fold change and urinary IL-10 change pattern were significantly associated with an ICR (P = 0.001 and P = 0.03, respectively). At a median (range) follow-up of 37 (20-88) months, 104 (56%) patients developed recurrence. Urinary IL-10, serum CTLA-4, T-bet , FoxP3 change patterns and GATA3 /T-bet ratio were significantly associated with tumour recurrence (P = 0.001, P = 0.001, P = 0.02, P = 0.009 and P = 0.001, respectively). Tumour progression occurred in 34 (18.3%) patients. Urinary IL-10, serum CTLA-4, serum T-bet change patterns and GATA3 /T-bet ratio were independent predictors of tumour progression (P = 0.001, P = 0.001, P = 0.02 and P = 0.001, respectively).

Conclusions: Urinary IL-10 and serum TNF-α can significantly predict ICR. Moreover, change pattern of urinary IL-10, serum CTLA-4, TFs (GATA3, T-bet and FoxP3) and GATA3 /T-bet ratio after BCG induction can independently predict further BCG response. These markers could be implemented in clinical practice when management options are discussed or in systems with severe BCG shortage.
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http://dx.doi.org/10.1111/bju.15582DOI Listing
August 2021

Myeloid-derived suppressor cells and regulatory T cells share common immunoregulatory pathways-related microRNAs that are dysregulated by acute lymphoblastic leukemia and chemotherapy.

Hum Immunol 2021 Jan 6;82(1):36-45. Epub 2020 Nov 6.

Immunology and Biotechnology Unit, Department of Zoology, Faculty of Science, Tanta University, Tanta, Egypt; Immunology Research Program, 57357 Children Cancer Hospital, Cairo, Egypt.

Background: Relapse remains a critical challenge in children with acute lymphoblastic leukemia (ALL). The emergence of immunoregulatory cells, including myeloid-derived suppressor cells (MDSCs), and T regulatory (T) cells, has been considered one potential mechanism of relapse in children with ALL.

Aim: This study aimed to address the microRNAs (miRNAs) related to MDSCs and T cells and to explore their targeted immunoregulatory pathways.

Methods: Affymetrix microarray was used for global miRNA profiling in B-ALL pediatric patients before, during, and after induction of chemotherapy. Bioinformatics analysis was performed on MDSCs and T cells-related dysregulated miRNAs, and miR-Pathway analysis was performed to explore their targeted immunoregulatory pathways.

Results: 516 miRNAs were dysregulated in ALL patients as compared to the healthy donor. Among them, 13 miRNAs and 8 miRNAs related to MDSCs and T cells, respectively, were common in all patients. Besides, 12 miRNAs were shared between MDSCs and T cells; 4 of them were common in all patients. Four immune-related pathways; TNF, TGF-β, FoxO, and Hippo were found implicated.

Conclusion: Our pilot study concluded certain miRNAs related to MDSCs and T cells, these miRNAs were linked to immunoregulatory pathways. Our results open avenues for testing those miRNA as molecular biomarkers for the immunosuppressive tumor microenvironment.
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http://dx.doi.org/10.1016/j.humimm.2020.10.009DOI Listing
January 2021

WITHDRAWN: The effect of anti IL-2/IL-2 complex versus stand-alone low dose of IL-2 on imiquimod induced psoriasis like skin inflammation model.

Immunol Lett 2020 Sep 16. Epub 2020 Sep 16.

Department of Dermatology and Venereology, Tanta University Hospital, Faculty of Medicine, Tanta University, Tanta, Egypt.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
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http://dx.doi.org/10.1016/j.imlet.2020.09.003DOI Listing
September 2020

The Antidiabetic Metformin as an Adjunct to Antidepressants in Patients with Major Depressive Disorder: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial.

Neurotherapeutics 2020 10;17(4):1897-1906

Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasaa, Egypt.

Metformin (MET) has been reported to have antidepressant effects in animal models and in diabetic patients with depression, owing to its anti-inflammatory, antioxidant, and neuroprotective activity. Accordingly, we proposed that MET would show antidepressant effects in patients with major depressive disorder (MDD) without other comorbidities. In this double-blind placebo-controlled study, 80 adult outpatients with MDD (DSM-IV criteria) and a Hamilton Depression Rating Scale (HAM-D) score >18 were randomized to receive fluoxetine 20 mg once daily plus placebo (n = 40) or fluoxetine 20 mg once daily plus MET 1000 mg once daily for 12 weeks. Patients were assessed by HAM-D score (weeks 0, 4, 8, and 12). The serum levels of TNF-α, IL-1β, IL-6, IGF-1, MDA, CRP, BDNF, and serotonin were measured before and after therapy. Mixed-effects model repeated-measures analysis of covariance was used to compare the HAM-D scores and the biological markers between the two groups. After 4, 8 and 12 weeks, patients in the MET group showed a statistically significant decline in HAM-D score relative to the placebo group (least squares mean difference [LSMD] -2.347, p = 0.000, LSMD -3.369, p = 0.000, and LSMD -3.454, p = 0.000, respectively). Response and remission rates were significantly higher in the MET group (89% and 81%, respectively) than in the placebo group (59% and 46%, respectively). Moreover, the MET group was superior in conserving the measured biological markers compared with the placebo group. Our findings suggest MET as a promising, effective, and safe short-term adjunctive approach in nondiabetic MDD patients. Trial registration ID: NCT04088448.
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http://dx.doi.org/10.1007/s13311-020-00878-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851215PMC
October 2020

Thymoquinone and pentoxifylline enhance the chemotherapeutic effect of cisplatin by targeting Notch signaling pathway in mice.

Life Sci 2020 Mar 14;244:117299. Epub 2020 Jan 14.

Biochemistry Department, Faculty of Pharmacy, Suez Canal University, Egypt.

Aims: Notch signaling is highly implicated in several cancers and chemoresistance. Therefore, Notch-targeted therapies might be beneficial in enhancing chemotherapeutic effect and cancer regression. This study aimed to investigate implication of Notch in development and progression of solid Ehrlich carcinoma (SEC) and enhancement of anticancer effect of cisplatin (CIS) by addition of thymoquinone (TQ) and pentoxifylline (PTX) through modulation of Notch.

Main Methods: SEC was induced in mice as model for mammary carcinoma by s.c. injection of 1 × 10 Ehrlich cells into back of the mice. On 12 day, solid tumor was developed and mice were divided into seven groups; tumor control, early CIS (ECIS), ECIS + ETQ, ECIS + ETQ + EPTX, late CIS (LCIS), LCIS + LTQ, and LCIS + LTQ + LPTX. Early treatment was started on 12 day, whereas late treatment was begun on 19 day from tumor inoculation. At the endpoint, samples were collected for detection of Notch1, Hes1, Jagged1, β-catenin, TNF-α, IL-6, IFN-γ, IL-2, VEGF, apoptosis, CD4, and CD8.

Key Findings: Adding PTX and TQ to CIS significantly reduced Notch1, Hes1, Jagged1, β-catenin, TNF-α, IL-6, IFN-γ, and VEGF with increment in IL-2, CD4, CD8, and apoptotic cells. Moreover, early treated groups showed remarkable attenuation in tumor growth and the relevant parameters compared to their counterpart later groups.

Significance: Addition of PTX with TQ to CIS showed a synergistic chemotherapeutic action and induced better oncostatic effect mainly through Notch suppression. Consequently, shutting Notch could be of great interest in promoting chemosensetivity and cancer control.
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http://dx.doi.org/10.1016/j.lfs.2020.117299DOI Listing
March 2020

Loading of doxorubicin and thymoquinone with F2 gel nanofibers improves the antitumor activity and ameliorates doxorubicin-associated nephrotoxicity.

Life Sci 2018 Aug 6;207:461-470. Epub 2018 Jun 6.

Biochemistry Department, Faculty of Pharmacy, Menoufia University, Egypt.

Aims: This study aimed to elucidate the benefits of nanoformulation of doxorubicin (DOX) and thymoquinone (TQ) loaded with nanofibers of poly-N-acetyl glucosamine (pGlcNAc), which is known as F2 gel, over their conventional free forms. Moreover, evaluate the role of TQ in improving chemotherapeutic effect and ameliorating nephrotoxicity of DOX.

Main Methods: The drugs were loaded into F2 gel followed by measurement of physicochemical characterization. Next, MCF-7 and HEPG2 cells were treated with the prepared formulations and assessed for apoptosis alongside with cellular proliferation. Furthermore, we experimentally induced Heps liver carcinoma in mice and at the end of the treatment, mice were sacrificed and serum samples were used to assess nephrotoxicity markers; blood urea nitrogen (BUN) and creatinine. Additionally, renal tissue was used for determination of oxidative markers and antioxidant enzymes; whereas, tumor tissue was utilized to measure nuclear factor kappa B (NF-κB) and caspase 3.

Key Findings: Nanoformulation showed dramatic increase in apoptosis, caspase 3, and antioxidant enzymes; in contrast to, dramatic fall in cell viability, tumor volume, oxidative and nephrotoxicity markers, and NF-κB compared to corresponding free therapies. Combined therapy was superior in conserving the measured parameters compared to other treated groups.

Significance: F2 gel loaded with DOX and TQ revealed enhanced antitumor activity with minimal toxicity. Moreover, using TQ as an adjuvant with DOX could augment its cytotoxicity and ameliorate nephrotoxicity.
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http://dx.doi.org/10.1016/j.lfs.2018.06.008DOI Listing
August 2018

Chemotherapy alters the increased numbers of myeloid-derived suppressor and regulatory T cells in children with acute lymphoblastic leukemia.

Immunopharmacol Immunotoxicol 2018 Apr 1;40(2):158-167. Epub 2018 Feb 1.

a Center of Excellence in Cancer Research (CECR), Tanta University , Tanta , Egypt.

Introduction: Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children. The precise mechanism behind the relapse in this disease is not clearly known. One possible mechanism could be the accumulation of immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs) and T regulatory cells (T) which we and others have reported to mediate suppression of anti-tumor immune responses.

Aim: In this study, we aimed to analyze the numbers of these cells in a population of B-ALL pediatric patients.

Methods: Peripheral blood samples withdrawn from B-ALL pediatric patients (n = 45 before, during and after the induction phase of chemotherapy. Using multi parametric flow cytometric analysis. MDSCs were identified as LinHLA-DRCD33CD11b; and T cells were defined as CD4CD25CD127.

Results: Early diagnosed B-ALL patients showed significant increases in the numbers of MDSCs and T as compared to healthy volunteers. During induction of chemotherapy, however, the patients showed higher and lower numbers of MDSCs and T cells, respectively as compared to early diagnosed patients (i.e., before chemotherapy). After induction of chemotherapy, the numbers of MDSCs and T cells showed higher increases and decreases, respectively as compared to the numbers in patients during chemotherapy.

Conclusion: Our results indicate that B-ALL patients harbor high numbers of both MDSCs and T cells. This pilot study opens a new avenue to investigate the mechanism mediating the emergence of these cells on larger number of B-ALL patients at different treatment stages.
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http://dx.doi.org/10.1080/08923973.2018.1424897DOI Listing
April 2018

High numbers of myeloid derived suppressor cells in peripheral blood and ascitic fluid of cirrhotic and HCC patients.

Immunol Invest 2018 Feb 28;47(2):169-180. Epub 2017 Nov 28.

a Faculty of Medicine, Department of Tropical Medicine , Tanta University , Tanta , Egypt.

Background: Hepatocellular carcinoma (HCC) is the 3rd most common cause of cancer-related death worldwide. It has evolved different immune escape mechanisms, which might include emergence of lymphoid and myeloid regulatory cells. Aim of this work: To determine the numbers of Myeloid-derived suppressor cells (MDSCs) in peripheral blood and ascitic fluid in cirrhosis and HCC and their relation to IFN-γ and α-fetoprotein (α-FP).

Patients And Methods: Sixty individuals were enrolled in this study; forty cirrhotic patients with ascites; twenty without HCC (Group I), and twenty with HCC (group II) as well as twenty healthy individuals as a control group (group III). The phenotype and numbers of MDSCs were analyzed in peripheral blood of all the individuals and ascitic fluid of the patients using flow cytometry. Intracellular IFN-γ and serum alfa-fetoprotein were measured.

Results: Significant increases in the relative and the mean number of peripheral blood MDSCs were found in the cirrhosis and HCC groups than in the control group, with the HCC group showing the highest number. MDSC count was negatively correlated with IFN-γ levels, while α-FP was positively correlated with MDSC% in the HCC group. MDSC count was low in ascitic fluid of both HCC and cirrhosis groups with no significant difference between the 2 groups.

Conclusion: A high frequency of MDSCs was detected in the peripheral blood of cirrhotic and HCC patients, indicating presence of immunosuppressive arms. These cells could be targeted to develop a new effective immunotherapy or an adjuvant to current therapies.
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http://dx.doi.org/10.1080/08820139.2017.1407787DOI Listing
February 2018

Enhanced anticancer effect and reduced toxicity of doxorubicin in combination with thymoquinone released from poly-N-acetyl glucosamine nanomatrix in mice bearing solid Ehrlish carcinoma.

Eur J Pharm Sci 2017 Nov 7;109:525-532. Epub 2017 Sep 7.

Biochemistry Department, Faculty of Pharmacy, Menoufia University, Egypt. Electronic address:

The incidence of breast cancer remarkably increases all over the world. Therefore, there is a great demand to introduce new approaches into cancer treatment field. The current study was designated to evaluate the role of doxorubicin (DOX) and/or thymoquinone (TQ) nanomatrix in potentiating the cytotoxicity of either drug, and to investigate the ability of TQ to reduce cardiotoxicity of DOX in solid Ehrlich carcinoma (SEC)-bearing mice. DOX and TQ were loaded into F2 gel, which is a fully-acetylated poly-N-acetyl glucosamine nanofiber. SEC was induced in female albino mice as a model for experimentally induced breast cancer. Mice were randomly divided into eight groups (n=10): normal control, tumor control, F2 gel, free DOX, DOX+F2 gel, free TQ, TQ+F2 gel, and DOX+TQ+F2 gel. On day 28th from tumor inoculation, mice were sacrificed and blood samples were collected for measurement of the cardiac markers; lactate dehydrogenase (LDH) and creatine kinase (CK-MB). In addition, cardiac tissue was utilized for determination of lipid peroxide, and tumor tissue was used for measurement of anti-apoptotic protein Bcl-2 as well as gene expression of the tumor suppressor gene P53. DOX and/or TQ showed a significant reduction in tumor volume, cardiac markers, tumor Bcl-2, and P53 upregulation compared to free conventional therapies. Co-treatment with DOX+TQ+F2 gel was superior to all other groups in exerting beneficial effects. Use of TQ as an adjuvant therapy with DOX could improve its cytotoxic effects and limit its cardiac toxicity. Furthermore, loading of DOX and/or TQ into F2 gel showed a remarkable anti-cancer activity.
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http://dx.doi.org/10.1016/j.ejps.2017.09.012DOI Listing
November 2017

IFN-α-based treatment of patients with chronic HCV show increased levels of cells with myeloid-derived suppressor cell phenotype and of IDO and NOS.

Immunopharmacol Immunotoxicol 2017 Aug 4;39(4):188-198. Epub 2017 May 4.

f City of Scientific Research and Technological Applications , Pharmaceutical and Fermentation Industries Development Center , New Burg El Arab , Egypt.

Introduction: Hepatitis C virus (HCV) infection causes chronic hepatitis, which is often associated with suppressed anti-HCV immune responses. We have recently reported accumulation of myeloid-derived suppressor cells (MDSCs) and suppressed immunity in cancer patients.

Aim: The main aim of this study was to determine whether chronic HCV patients harbor high of MDSCs in general and in nonresponders to IFN-based therapy in particular as well as to analyze the immune suppressive molecules.

Methods: Peripheral blood samples withdrawn from 154 patients with chronic HCV infection and were categorized into responders and nonresponders based on viral titer upon IFN-α treatment.

Results: The relative and absolute numbers of MDSCs defined as Lin/HLA-DR/CD33/CD11b increased in all HCV patients, where they were higher in nonresponders than in responders. Additionally, the levels of MDSCs after 4-6 months of treatment in responders were lower than during the course of treatment. The responders also showed higher levels of IL-2 coincided with increased numbers of dendritic cells (DCs), CD4 and CD8 T cells. The levels of total NOS and IDO were also higher in nonresponders as compared to responders and healthy controls, while the expression levels of CD3ζ was lower in responders as compared to nonresponders and healthy volunteers.

Conclusion: Chronic HCV patients harbor high numbers of MDSCs, which are higher in nonresponders than in responders. The higher numbers of MDSCs associated with increases in the suppressing factors.
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http://dx.doi.org/10.1080/08923973.2017.1320670DOI Listing
August 2017

Immunomodulatory effects of IL-12 released from poly-N-acetyl glucosamine gel matrix during schistosomiasis infection.

Cytotechnology 2014 Aug 26;66(4):667-75. Epub 2013 Jul 26.

Immunology and Biotechnology Division, Department of Zoology, Faculty of Science, Tanta University, Tanta, Egypt,

We have reported recently that Interleukin-12 (IL-12) released from poly-N-acetyl glucosamine gel matrix (F2 gel/IL-12) is more effective than free IL-12 to enhance vaccination of mice with Schistosoma soluble worm antigen preparation. The aim of this study is to evaluate the effect of F2 gel/IL-12 on the inflammatory responses in mice undergoing schistosomiasis infection in absence of vaccination. To achieve this, mice undergoing Schistosoma mansoni infection or cured from this infection, after treatment with praziquantil (PZQ), were treated with subcutaneous injection of IL-12 for 3 consecutive days or once with F2 gel loaded with IL-12 (F2 gel/IL-12). The treatment was started on day 35 days after infection. For infection, mice were infected with 100 cercariae of S. mansoni using tail immersion method. We found that treatment with F2 gel/IL-12 induced significant decreases in the egg burden with a moderate reduction in the size of granuloma and decrease in the cellular granulomatous reaction in the lung as compared to infected mice treated with IL-12. These effects of F2 gel/IL-12 were more pronounced in infected mice previously treated with the anti-schistosomal drug PZQ. The total numbers of white blood cells in all treated mice showed similar profile. Treatment with IL-12 or F2 gel/IL-12, however, showed significant reduction in the number of mononuclear cells when compared with non-treated infected mice. In conclusion, this study showed the ability of IL-12 released from F2 gel to lower the inflammatory response to Schistosoma infection even in absence of vaccination.
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http://dx.doi.org/10.1007/s10616-013-9620-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082772PMC
August 2014

Active immunization against tumor necrosis factor-alpha decreases proinflammatory cytokines, oxidative stress mediators and adhesion molecules risk factors in streptozotocin-induced diabetic rats.

Endocr Metab Immune Disord Drug Targets 2013 Sep;13(3):269-74

Department of Zoology, Faculty of Science, Damanhour University, Damanhour, Egypt.

Unlabelled: Diabetes is now one of the most common un-communicable diseases worldwide. Few studies have dealt specifically with the potential therapeutic effect of TNF-α suppressor to decrease oxidative stress markers in patients with diabetes. The aim of this study was to investigate the potential therapeutic and toxic effect of the direct injection of the anti-TNF-α on oxidative stress mediators, proinflammatory cytokines and vascular risk factors associated with diabetes on diabetic rats.

Methods: diabetes was induced by streptozotocin, three weeks after the - induction of diabetes, a polyclonal anti-mouse/rat TNF-α rabbit serum was injected in the treated group and sacrificed after 4 weeks. The expression of TNF-α mRNA was measured by RT-PCR. The levels of TNF-α, VEGF, IL-2, IL- 6, HSP-70, troponin-t, 8-OHdG, ICAM-1 and VCAM-1 were evaluated using ELISA. Myeloperoxiase (MPO) and total peroxides (TPs) levels were estimated by biochemical reactions.

Results: the treatment of diabetic rats with the anti-TNF-α caused a significant decrease in the TNF-α mRNA expression, which were paralleled with the decreased levels of TNF-α, IL-6, MOP, HSP-70, ICAM-1, VCAM-1, troponin-t and 8-OHdG in the blood serum. On the contrary, all were highly expressed in the diabetic group that may be the leading reasons for the DNA damage and cell loss. Data revealed that TNF-α, HSP-70, IL-6, MPO and adhesion molecules when expressed in diabetic rats, collectively induce dramatic changes.

Conclusion: these new findings suggested that targeting TNF-α could effectively reduce expressions of MCP-1, HSP-70, troponin-t, 8-OHdG and VCAM- 1, along with prominent reduction in MPO and IL-6 levels.
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http://dx.doi.org/10.2174/18715303113139990039DOI Listing
September 2013

Kinetics of rebounding of lymphoid and myeloid cells in mouse peripheral blood, spleen and bone marrow after treatment with cyclophosphamide.

Cell Immunol 2012 Mar-Apr;276(1-2):67-74. Epub 2012 Apr 11.

Zoology Department, Faculty of Science, Tanta University, Tanta, Egypt.

Recently, we showed that post cyclophosphamide (CTX) microenvironment benefits the function of transferred T cells. Analysis of the kinetics of cellular recovery after CTX treatment showed that a single 4 mg/mouse CTX treatment decreased the absolute number of leukocytes in the peripheral blood (PBL) at days 3-15, and in the spleen and bone marrow (BM) at days 3-6. The absolute numbers of CD11c(+)CD11b(-) and CD11c(+)CD11b(+) dendritic cells (DCs), CD11b(+) and Ly6G(+) myeloid cells, T and B cells, CD4(+)CD25(+) T regulatory (T(reg)) cells, and NK1.1(+) cells also decreased. The cell numbers returned to control levels during the recovery phase. The absolute numbers of B cells remained low for 3 weeks. The numbers of DCs increased in PBL and spleen at day 9 but returned to control levels at day 15. These data indicate that CTX alters the cellular microenvironment in kinetics that might be precisely targeted to benefit the host.
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http://dx.doi.org/10.1016/j.cellimm.2012.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787597PMC
October 2012

Synergy of brief activation of CD8 T-cells in the presence of IL-12 and adoptive transfer into lymphopenic hosts promotes tumor clearance and anti-tumor memory.

Am J Cancer Res 2011 Aug;1(7):882-96

Department of Medicine, Division of Hematology/Oncology, Sylvester Cancer Center, University of Miami, Miami, FL33136, USA.

Adoptive T-cell therapy holds great promise for the treatment of metastatic melanoma. However, prohibitive costs associated with current technology required for culture and expansion of tumor-reactive T-cells, the need for intense preconditioning regimens to induce lymphopenia, and the unpredictable anti-tumor effect of adoptively transferred T-cells remain significant impediments for its clinical implementation. Here we report a simplified combinatorial approach that involves short activation of CD8(+) T cells in the presence of IL-12 followed by adoptive transfer into tumor bearing animals after a single injection of cyclophosphamide. This approach resulted in complete eradication of B16 melanoma, and the establishment of long term immunological memory capable of fully protecting mice after a second B16 melanoma challenge. The activated donor cells were unique because they simultaneously exhibited traits for cytotoxic effector function, central memory-like, homing, and senescence. After tumor eradication and within three months after transfer, CD8+ cells exhibited a conventional memory CTL phenotype. Moreover, these memory CTLs acquired functional attributes characteristic of memory stem cells, including the ability to resist chemotherapy-induced toxicity. Our results suggest that short-term T-cell receptor signaling in the presence of IL-12 promotes promiscuous qualities in naïve CTL which - upon transfer into lymphopenic hosts- are sufficient to eradicate tumors and generate life-long tumor-specific memory.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170749PMC
August 2011
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