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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 4  |  Issue : 5  |  Page : 603-609

Children with acute lymphoblastic leukemia show high numbers of CD4+ and CD8+ T-cells which are reduced by conventional chemotherapy


1 Center of Excellence in Cancer Research, Tanta University Educational Hospital; Immunology and Biotechnology Division, Zoology Department, Faculty of Science, Tanta University, Tanta, Egypt
2 Center of Excellence in Cancer Research, Tanta University Educational Hospital; Hematology/Oncology Unit, Pediatric Department, Faculty of Medicine, Tanta University, Tanta, Egypt
3 Histology and Histochemistry Division, Zoology Department, Faculty of Science, Tanta University,Tanta, Egypt
4 Center of Excellence in Cancer Research, Tanta University Educational Hospital; Clinical Pathology, Faculty of Medicine, Medical Campus, Tanta University, Tanta, Egypt
5 Center of Excellence in Cancer Research, Tanta University Educational Hospital, Tanta, Egypt

Date of Web Publication9-Sep-2015

Correspondence Address:
Mohamed Labib Salem
Center of Excellence in Cancer Research, Tanta University Educational Hospital, Tanta, Egypt.
Egypt
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Source of Support: This work has been supported by a grant (ID number 5245) funded from the Science and Technology Development Fund, Ministry of Scientific Research, Egypt to Mohamed L. Salem, the Principal investigator of this project., Conflict of Interest: There are no conflicts of interest.


DOI: 10.4103/2278-0513.164717

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  Abstract 

Background: Acute lymphoblastic leukemia (ALL) is considered as one of the most common cancer in pediatric malignancies. Among ALL, B-cell Acute Lymphoblastic Leukemia (B-ALL) represents 80% to 85% of the childhood ALL.
Problem: Although anti B-ALL chemotherapy kill B-ALL, it associates with alteration in the numbers of CD4+ and CD8+ T-cells, and thus impacts the overall immunity.
Aim: To evaluate the impact of anti B-ALL on the numbers of CD4+ and CD8+ T-cells in correlation to the numbers of CD10+ B cells in B-ALL pediatric patients.
Materials and Methods: Peripheral blood samples were drawn from previously diagnosed B-ALL before (n = 10 cases) and after (n = 10 cases) chemotherapy as well as from healthy controls (n = 10 cases). The numbers of CD4+, CD8+ T-cells and CD10+ B cells were measured in these samples by flow cytometry.
Results: As expected, the numbers of CD10+ B-cells were increased in B-ALL patients before chemotherapy which were associated with increases in the numbers of CD4+ and CD8+ T-cells. Chemotherapy of B-ALL patients, during the induction phase, induced dramatic decreases in the numbers of CD10+ B cells, which were associated with decreases in the numbers of CD4+ and CD8+ T-cells. Tin spite of this alteration, the ratio of CD4/CD8 in B-ALL patients were remained similar before and after chemotherapy as compared to those in healthy controls.
Conclusion: Anti B-ALL chemotherapy induces alterations in the frequencies of T-cell subsets. Given the importance of these cells in anti-tumor immunity, our data may lead to further studies to investigate the different subsets of these cells, in particular regulatory T-cells.

Keywords: B-acute lymphoblastic leukemia, B-ALL, B-cells, cancer, CD10, CD4, CD8, chemotherapy, T-cells, Tregs


How to cite this article:
Salem ML, El-Shanshory MR, El-Desouki NI, Abdou SH, Attia MA, Zidan AAA, Mourad SS. Children with acute lymphoblastic leukemia show high numbers of CD4+ and CD8+ T-cells which are reduced by conventional chemotherapy. Clin Cancer Investig J 2015;4:603-9

How to cite this URL:
Salem ML, El-Shanshory MR, El-Desouki NI, Abdou SH, Attia MA, Zidan AAA, Mourad SS. Children with acute lymphoblastic leukemia show high numbers of CD4+ and CD8+ T-cells which are reduced by conventional chemotherapy. Clin Cancer Investig J [serial online] 2015 [cited 2019 Oct 17];4:603-9. Available from: http://www.ccij-online.org/text.asp?2015/4/5/603/164717




  Introduction Top


Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children,[1],[2] representing more than a quarter of all pediatric cancers.[2] Patients with ALL receive intensive courses of chemotherapy which are followed by a period of severe leukopenia,[3] even if those patients have a functional CD4+ and CD8+ T-cell system. The immature blasts in B-acute lymphoblastic leukemia (B-ALL) have no unique morphologic or cytochemical features.[3] Therefore, immunophenotyping of ALL has been routinely performed in the diagnostic evaluation, to determine the leukemic B-cells through specific surface markers associated with B-cell linage, including CD10+.[4] CD10 is commonly expressed on the majority of precursor B-ALL during the early stages of B-cell maturation and development.[5] Approximately three-quarters of patients express this common B-ALL precursor.[6] B-ALL cases which express CD10 have the best prognosis among B-ALL cases,[7] where absence of CD10 expression is associated with poor prognosis.[8]

Significant progress of treatment of pediatric B-cell malignancies including leukemia has been efficacious. However, many children with B-ALL still do not respond to the standard chemotherapy,[9] which is often associated with disturbance in the numbers of T-cell populations. This alteration in T-cells is likely to impact the endogenous anti B-ALL immunity as well as any trial of immunotherapy. Immunotherapy, in particular adoptive T-cell transfer, depends mainly on harvesting CD8+ cytotoxic T-cells from the patient, activating them in vitro and infusing them back to the same patients with the main goal to attack cancer cells by the adoptively transferred T-cells.[10] Therefore, understanding how chemotherapy alters T-cell population upon chemotherapy is crucial to design effective T-cell-based immunotherapy since the alteration in T-cell numbers may associate with emergence of regulatory CD4+ T (Treg) cells with immunosuppressive effects. Treg cells are defined as inhibitor of immune system due to their immunosuppressive mechanism with the progressiveness of malignancy.[11] Indeed, previous results reported the emergence of these Treg cells in some hematological malignancies with a poor prognosis.[12]

In this study, we investigated the numbers of CD4+ and CD8+ cells in the peripheral blood of pediatric patient with B-ALL before and after the induction of chemotherapy. Our results showed a correlation between the impact of chemotherapy on leukemic CD10+ B cells and the alteration in the numbers of CD4+ and CD8+ T-cells. Our results open new avenues for further studies to investigate the subsets of these cells in particular, regulatory T-cells.


  Materials and Methods Top


Patients

Patients included in this study were risk stratified according to risk classification system and were treated according to treatment protocols including high risk pre B-ALL protocol, standard risk pre B-ALL. The research study was approved by the Local Ethics Committee, Faculty of Medicine, Tanta University and informed consent was obtained from all patients before participation. The study was conducted among patients n = 20; before (n = 10) and after (n = 10) the induction of chemotherapy;

mean age = 6, as compared to healthy subjects (n = 10); mean age = 5. Patients were recruited from Hematology/Oncology Unit, Pediatric Departments, Tanta University Hospital, Tanta Cancer Center, Tanta, Egypt.

Patient diagnosis

Bone marrow biopsy was used to confirm the presence of leukemic blasts using laboratory microscopic investigation followed by immunophenotyping using flow cytometry in order to identify the subtype of acute leukemia using the routinely diagnostic antibodies, including CD10, CD19, CD2, CD7, CD13, CD117, CD33, CD14, CD64, CD34, HLA-DR and CD45 (BD Biosciences, CA, USA).

B-acute lymphoblastic leukemia treatment protocol

Patients were treated according to treatment protocols including high risk pre B-ALL protocol, standard risk pre B-ALL. Follow-up of patients was carried out clinically and by blast count in bone marrow on day 21 after induction chemotherapy. The treatment included: Vincristine 1.5 mg/kg/m2/week IV (days 0, 7, 14, 21, 28, 35), doxorubicin 25 mg/m2/week IV infusion (days 0, 7, 14, 21, 28, 35), L-asparginase 6000 U/m2 SC on alternate days for 10 doses, and prednisone 40 mg/m2/day for 6 weeks orally. On day 21, bone marrow aspiration was done. In non responding cases, we added etopsoide 100 mg/m2/dose IV (days 22, 25, 29), cyclophosphamide 750 mg/m2/dose IV infusion (days 22, 25, 29), aracytin 100/m2/dose IV (days 22, 25, 29), and high-dose methotrexate 5 g/m2 over 4 h on day 28.

Reagents and antibodies

Monoclonal antibodies against surface markers, including CD10, CD19, CD2, CD7, CD13, CD117, CD33, CD14, CD64, CD34, HLA-DR and CD45 (BD Biosciences, CA, USA), were used in diagnosis of acute leukemia. For identification of T-Cell populations, anti CD4 (BD Biosciences), anti CD8 (BD Biosciences) were used in samples processing. BD FACS lysing buffer was used in RBSs lysis and phosphate buffer saline (PBS) was used in sample washing and suspension.

Flow cytometric analysis

Bone marrow biopsy and immunophenotyping were performed in order to identify the type of acute leukemia using the routinely diagnostic antibodies. For identification of T-cells subsets, fresh venous peripheral blood samples were collected in EDTA tubes. 100 µL of blood was stained with 5 µL of each antibody in the staining tubes, the tubes were incubated in dark conditions for 20 min then samples was mixed with BD FACS lysing solution (1X) then incubated for 15 min in the dark conditions. Samples then centrifuged at 1250 r/min for 5 min, the supernatant was discarded to remove the lysed RBCs. PBS was added then samples were centrifuged at 1250 r/min for 5 min then the supernatant was discarded to remove any remained debris or RBCs then the pellets were resuspended in 350 µL of PBS. The absolute numbers of cells were calculated using the following formula: Percentage of cells × total number of white blood cells/100.

Statistical analysis

The clinical data were collected along the study and analyzed for each patient. The data were represented as mean ± standard deviation and analyzes of frequencies for statically significant differences were performed with a one-way analysis of variance (ANOVA). We assumed that frequencies of T-cell and B-cell in the peripheral blood of B-ALL pediatric patients did not follow a normal distribution; experimental differences over the healthy control volunteers were analyzed by the Student's t-test. Significant differences were defined as P < 0.05 (P values below 0.05 were considered significant).


  Results Top


Patient demographics before and after induction chemotherapy

The mean age, sex, total blast count and whether these patients diagnosed with splenohepatomegaly [Table 1].
Table 1: B-ALL pediatric patients‘ demographic data showing age, sex, diagnosis with hepato-splenomegaly and total blast count

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Increases in the numbers of B cells expressing CD10+ B-cells in the peripheral blood of B-acute lymphoblastic leukemia patients

As shown in [Figure 1] and [Figure 2]a, analysis of the percentages showed significant increases in the numbers of CD10+ B-cells in B-ALL patients before chemotherapy as compared to healthy donors (75 ± 28.2 vs. 15.8 ± 3.23, P < 0.001). The percentages of CD10+ cells decreased upon induction of chemotherapy as compared to healthy donors; (10.5 ± 6.8 vs. 15.8 ± 3.23). The absolute numbers of CD10+ B-cells showed significant increases before chemotherapy as compared to healthy donors (3343.6 ± 2353 vs. 463.8 ± 223.4, P < 0.001) and these numbers turned to decrease after induction of chemotherapy when compared to healthy donors (151.4 ± 77.4 vs. 463.8 ± 223.4) as shown in [Figure 2]b.
Figure 1: A representative flow cytometric analysis of CD10+ B-cells in pediatrics patient with B-acute lymphoblastic leukemia showing the expression of CD10+ B-cells in five healthy donors (a), five patients before induction of chemotherapy (b) and five patients after induction of chemotherapy (c)

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Figure 2: The numbers of CD10+ B cells in B-acute lymphoblastic leukemia patients. (a) The percentages of CD10+ B-cells in B-acute lymphoblastic leukemia pediatric patients before and after induction of chemotherapy as compared to healthy control donors "control." (b) The absolute (abs.) numbers of these cells in the same patients as compared to healthy control volunteers "control." The absolute numbers of CD10+ cells were calculated as: (Total white blood cells count [cells/µL] × percent of CD10+)/100

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Increases in the numbers of CD4+ T-cells in the peripheral blood of B-acute lymphoblastic leukemia pediatric patients

As shown in [Figure 3], [Figure 4]a and [Figure 4]b, the percentages of CD4+ T-cells increased in patients with B-ALL before induction phase of chemotherapy when compared to healthy donors (17.6 ± 5.58 vs. 14.6 ± 1.86) and these percentages decreased after induction of chemotherapy when compared to healthy donors (14.4 ± 1.23 vs. 14.6 ± 1.86). As shown in [Figure 4]c, patients with B-ALL showed significantly higher absolute numbers of CD4+ T-cell before chemotherapy as compared to healthy donors (858.6 ± 517.7 vs. 472.15 ± 295.12, P < 0.05) and decreases in absolute numbers after induction of chemotherapy as compared to healthy donors (293.8 ± 105.9 vs. 472.15 ± 295.12).
Figure 3: A representative flow cytometric analysis of CD4+ and CD8+ T-cells in pediatric patients with B-acute lymphoblastic leukemia showing the expression of CD4+ and CD8+ in five healthy donors (a), five patients before induction of chemotherapy (b) and five patients after induction of chemotherapy (c)

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Figure 4: The numbers of CD4+ and CD8+ T-cells in B-acute lymphoblastic leukemia patients as compared to healthy control volunteers. (a) The percentages of CD4+ and CD8+ T-cells in all B-acute lymphoblastic leukemia pediatric patients as compared to healthy donors "control." (b) The percentages of CD4+ and CD8+ T-cells in patients before and after induction of chemotherapy as compared to healthy donors "control." (c) The absolute (abs.) numbers of CD4+ and CD8+ T-cells in patients before and after induction of chemotherapy as compared to healthy donors "control"

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Increase in expression of CD8+ T-cells in the peripheral blood of B-acute lymphoblastic leukemia pediatric patients

As shown in [Figure 3], [Figure 4]a and [Figure 4]b, the percentages of CD8+ T-cells increased in patients with B-ALL before induction phase of chemotherapy as compared to healthy donors and these percentages decreased after induction of chemotherapy as compared to healthy. As shown in [Figure 4]c, patients with B-ALL showed significantly higher absolute numbers of CD8+ T-cell before chemotherapy as compared to healthy donors (590.31 ± 317 vs. 472.15 ± 295.12, P < 0.05) and these numbers turned to decrease after induction of chemotherapy as compared to healthy donors (234.5 ± 90.16 vs. 472.15 ± 295.12).

The ratio of CD4/CD8 in the peripheral blood of B-acute lymphoblastic leukemia pediatric patients

We investigated the ratios of CD4/CD8 in pediatric patients before and after induction of chemotherapy. We found that the ratio of CD4:CD8 before chemotherapy was 1.3 as compared to 1.4 in healthy donors. The ratio of CD4:CD8 after induction of chemotherapy was 1.35 as compared to 1.4 in healthy donors as shown in [Table 2].
Table 2: The ratios of CD4/CD8 in the peripheral blood of healthy CTRL volunteers as well as B-ALL pediatric patients before and after induction of chemotherapy

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Correlation between CD4+, CD8+ T-cells and CD10+ B-cells in the peripheral blood of B-acute lymphoblastic leukemia pediatric patients

ANOVA test was used to analyze the correlation between CD4+, CD8+ T-cells and CD10+ B-cells in the peripheral blood of B-ALL pediatric patients. We found that the increase in the numbers of CD4+ and CD8+ T-cells before induction of chemotherapy was associated with an increase in the numbers of CD10+ B-cells. The differences between the percentages and absolute numbers of CD4+, CD8+ T-cells versus CD10+ B-cells are shown in [Table 3].
Table 3: Differences between CD4+, CD8+ T-cells versus CD10+ B-cells, percentages and absolute numbers in B-ALL pediatric patients before and after induction of chemotherapy

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  Discussion Top


We performed immunophenotyping analysis on the peripheral blood of children patients with B-ALL based on surface markers detection. This analysis was carried out to determine the frequencies of CD4+, CD8+ T-cells and CD10+ B-cells and to show the correlation between these cells before and after induction of chemotherapy. The results showed that the increase in the numbers of CD10+ B-cells was associated with significant increases in the numbers of CD4+, CD8+ T-cells. As expected, we found that the numbers of CD10+ B-cells increased in B-ALL patients before chemotherapy coinciding with increase in the numbers of CD4+ and CD8+ T-cells. Induction of chemotherapy induced dramatic decreases in the numbers of CD10+ B-cells, coinciding with increases in the numbers of both CD4+ and CD8+ T-cells. Our results conclude that anti B-ALL chemotherapy induces alterations in the T-cells subsets, opening a new avenue to investigate the phenotypes of different subsets of these cells in particular regulatory T-cells.

Consistent with previous studies,[13],[14],[15],[16],[17],[18] we found that the ratios of CD4+, CD8+ T-cells and CD10+ B-cells are higher in patients with B-ALL at diagnosis. These numbers were reduced upon treatment with chemotherapy. CD4+ effector T-cells have previously been suggested to play an important role in anti-tumor immunity in different malignancies including B-ALL[19],[20] since they offer antigen-specific aid to tumor-reactive CD8+ T-cells, resulting in elimination of the leukemic lymphoblast during the induction of chemotherapy. Considerably, protective immune responses may actively hindered by local immunosuppression[21] in the peripheral blood of B-ALL patients. One of the best-defined mechanisms of local immunosuppression is the accumulation of Tregs with suppressive functions[22] due to either increases in the numbers of natural Treg cells or conversion of CD4+ T-cells to CD4+ Treg cells.

The immunosuppressive function of Treg cells are considered as part of CD4+ effector T-cells.[12] Although we have identified the phenotype of CD4+ T-cells in this study, it could be suggested that the increases in the numbers of CD4+ T-cells in our patients before chemotherapy might be a result of partial conversion of CD4+ T-cells into immunosuppressive Tregs.[23] Current studies by our group are ongoing to test this hypothesis. Furthermore the decreases in the numbers of CD4+ T-cells subsequent to induction of chemotherapy might be due to the cyclophosphamide that is included in this treatment protocol since this drug has been reported in previous studies to decrease the frequencies of CD4+ T-cells and Treg cells.[24]

The affinity of CD4+ and CD8+ T-cells to functionally interact with leukemic cells needs to be determined in order to develop effective immunotherapeutic strategies in B-ALL patients.[25]

CD8+ co-receptor is predominantly expressed on the surface of cytotoxic T-cells. Previous studies have reported that T-cell numbers, particularly CD8+ in diagnosis correlate with prognosis in some hematological malignancies, including lymphoma and acute lymphoblastic leukemia.[26] Furthermore, previous publications by our and other groups established that cytotoxic CD8+ T-cells are the main killer cells that attack cancer cells specifically and cure advanced tumor.[27],[28],[29],[30],[31],[32],[33] Accordingly, adoptive cell therapy utilizing CD8+ T-cells has shown promising application in clinical setting.[34] This application has been reflected recently by the use of chimeric antigen receptor therapy for immunotherapy that shows great promise for ALL by engineering CD8+ T-cells to recognize CD19+ B cells resulting in specific killing of B cell leukemia and lymphoma.[25] As such, the alteration in both CD4+ and CD8+ T-cells in B-ALL patients before and after chemotherapy is of a great importance for the clinical application of immunotherapy.


  Conclusion Top


Our study illustrates the alterations in both CD4+ and CD8+ T-cell subsets in B-ALL patients before and after induction of chemotherapy, where these cells increased and decreased before and after induction of chemotherapy, respectively. Further studies with larger numbers of patients are considered to specifically determine the subsets of T-cell subsets, in particular Treg cells in B-ALL at different stages of chemotherapy.

Acknowledgments

This work has been supported by a grant (ID number 5245) funded from the Science and Technology Development Fund, Ministry of Scientific Research, Egypt to Mohamed L. Salem, the Principal investigator of this project.

This work has been supported by a grant (ID number 5245) funded from the Science and Technology Development Fund, Ministry of Scientific Research, Egypt to Mohamed L. Salem, the Principal investigator of this project.

There are no conflicts of interest.



 
  References Top

1.
Wu CP, Qing X, Wu CY, Zhu H, Zhou HY. Immunophenotype and increased presence of CD4(+) CD25(+) regulatory T cells in patients with acute lymphoblastic leukemia. Oncol Lett 2012;3:421-4.  Back to cited text no. 1
    
2.
Woo JS, Alberti MO, Tirado CA. Childhood B-acute lymphoblastic leukemia: A genetic update. Exp Hematol Oncol 2014;3:16.  Back to cited text no. 2
    
3.
Friedmann AM, Weinstein HJ. The role of prognostic features in the treatment of childhood acute lymphoblastic leukemia. Oncologist 2000;5:321-8.  Back to cited text no. 3
    
4.
Ferreira-Facio CS, Milito C, Botafogo V, Fontana M, Thiago LS, Oliveira E, et al. Contribution of multiparameter flow cytometry immunophenotyping to the diagnostic screening and classification of pediatric cancer. PLoS One 2013;8:e55534.  Back to cited text no. 4
    
5.
Hoelzer D. Novel antibody-based therapies for acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2011;2011:243-9.  Back to cited text no. 5
    
6.
Rezazadeh D, Moradi MT, Kazemi A, Mansouri K. Childhood Pre-B acute lymphoblastic leukemia and glutathione S-transferase omega 1 and 2 polymorphisms. Int J Lab Hematol 2015;37:530-5.  Back to cited text no. 6
    
7.
Pui CH, Chessells JM, Camitta B, Baruchel A, Biondi A, Boyett JM, et al. Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements. Leukemia 2003;17:700-6.  Back to cited text no. 7
    
8.
Pieters R, Schrappe M, De Lorenzo P, Hann I, De Rossi G, Felice M, et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): An observational study and a multicentre randomised trial. Lancet 2007;370:240-50.  Back to cited text no. 8
    
9.
Jeha S. New therapeutic strategies in acute lymphoblastic leukemia. Semin Hematol 2009;46:76-88.  Back to cited text no. 9
    
10.
Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: A clinical path to effective cancer immunotherapy. Nat Rev Cancer 2008;8:299-308.  Back to cited text no. 10
    
11.
Jadidi-Niaragh F, Ghalamfarsa G, Yousefi M, Tabrizi MH, Shokri F. Regulatory T cells in chronic lymphocytic leukemia: Implication for immunotherapeutic interventions. Tumour Biol 2013;34:2031-9.  Back to cited text no. 11
    
12.
Lahjouji A, Bachir F, Bennani S, Quessar A, Amzazi S. The immunophenotype of adult T acute lymphoblastic leukemia in Morocco. Exp Oncol 2015;37:64-9.  Back to cited text no. 12
    
13.
Feuerer M, Beckhove P, Bai L, Solomayer EF, Bastert G, Diel IJ, et al. Therapy of human tumors in NOD/SCID mice with patient-derived reactivated memory T cells from bone marrow. Nat Med 2001;7:452-8.  Back to cited text no. 13
    
14.
Dhodapkar MV, Krasovsky J, Osman K, Geller MD. Vigorous premalignancy-specific effector T cell response in the bone marrow of patients with monoclonal gammopathy. J Exp Med 2003;198:1753-7.  Back to cited text no. 14
    
15.
Letsch A, Keilholz U, Assfalg G, Mailänder V, Thiel E, Scheibenbogen C. Bone marrow contains melanoma-reactive CD8+effector T cells and, compared with peripheral blood, enriched numbers of melanoma-reactive CD8+memory T cells. Cancer Res 2003;63:5582-6.  Back to cited text no. 15
    
16.
Gleissner B, Goekbuget N, Rieder H, Arnold R, Schwartz S, Diedrich H, et al. CD10- pre-B acute lymphoblastic leukemia (ALL) is a distinct high-risk subgroup of adult ALL associated with a high frequency of MLL aberrations: Results of the German Multicenter Trials for Adult ALL (GMALL). Blood 2005;106:4054-6.  Back to cited text no. 16
    
17.
Zhao HJ, Xu C, Chen J, Wu ZH, Xue HL, Tang JY, et al. Characterization of CD10 expression and its significance in minimal residual disease detection in childhood B-acute lymphoblastic leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2003;11:350-4.  Back to cited text no. 17
    
18.
Kebriaei P, Poon ML. Future of therapy in acute lymphoblastic leukemia (ALL) – Potential role of immune-based therapies. Curr Hematol Malig Rep 2015;10:76-85.  Back to cited text no. 18
    
19.
Mumberg D, Monach PA, Wanderling S, Philip M, Toledano AY, Schreiber RD, et al. CD4(+) T cells eliminate MHC class II-negative cancer cells in vivo by indirect effects of IFN-gamma. Proc Natl Acad Sci U S A 1999;96:8633-8.  Back to cited text no. 19
    
20.
Corthay A, Skovseth DK, Lundin KU, Røsjø E, Omholt H, Hofgaard PO, et al. Primary antitumor immune response mediated by CD4+T cells. Immunity 2005;22:371-83.  Back to cited text no. 20
    
21.
Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004;10:942-9.  Back to cited text no. 21
    
22.
Beyer M, Kochanek M, Giese T, Endl E, Weihrauch MR, Knolle PA, et al. In vivo peripheral expansion of naive CD4+CD25high FoxP3+regulatory T cells in patients with multiple myeloma. Blood 2006;107:3940-9.  Back to cited text no. 22
    
23.
Peng DJ, Liu R, Zou W. Regulatory T cells in human ovarian cancer. J Oncol 2012;2012:345164.  Back to cited text no. 23
    
24.
Sevko A, Sade-Feldman M, Kanterman J, Michels T, Falk CS, Umansky L, et al. Cyclophosphamide promotes chronic inflammation-dependent immunosuppression and prevents antitumor response in melanoma. J Invest Dermatol 2013;133:1610-9.  Back to cited text no. 24
    
25.
Boublikova L, Kalinova M, Ryan J, Quinn F, O'Marcaigh A, Smith O, et al. Wilms' tumor gene 1 (WT1) expression in childhood acute lymphoblastic leukemia: A wide range of WT1 expression levels, its impact on prognosis and minimal residual disease monitoring. Leukemia 2006;20:254-63.  Back to cited text no. 25
    
26.
Bindea G, Mlecnik B, Fridman WH, Galon J. The prognostic impact of anti-cancer immune response: A novel classification of cancer patients. Semin Immunopathol 2011;33:335-40.  Back to cited text no. 26
    
27.
Salem ML, Cole DJ. Dendritic cell recovery post-lymphodepletion: A potential mechanism for anti-cancer adoptive T cell therapy and vaccination. Cancer Immunol Immunother 2010;59:341-53.  Back to cited text no. 27
    
28.
Salem ML, Díaz-Montero CM, Al-Khami AA, El-Naggar SA, Naga O, Montero AJ, et al. Recovery from cyclophosphamide-induced lymphopenia results in expansion of immature dendritic cells which can mediate enhanced prime-boost vaccination antitumor responses in vivo when stimulated with the TLR3 agonist poly (I: C). J Immunol 2009;182:2030-40.  Back to cited text no. 28
    
29.
Salem ML, Kadima AN, El-Naggar SA, Rubinstein MP, Chen Y, Gillanders WE, et al. Defining the ability of cyclophosphamide preconditioning to enhance the antigen-specific CD8+T-cell response to peptide vaccination: Creation of a beneficial host microenvironment involving type I IFNs and myeloid cells. J Immunother 2007;30:40-53.  Back to cited text no. 29
    
30.
Rubinstein MP, Cloud CA, Garrett TE, Moore CJ, Schwartz KM, Johnson CB, et al. Ex vivo interleukin-12-priming during CD8(+) T cell activation dramatically improves adoptive T cell transfer antitumor efficacy in a lymphodepleted host. J Am Coll Surg 2012;214:700-7.  Back to cited text no. 30
    
31.
Salem ML, Kadima AN, Cole DJ, Gillanders WE. Defining the antigen-specific T-cell response to vaccination and poly (I: C)/TLR3 signaling: Evidence of enhanced primary and memory CD8 T-cell responses and antitumor immunity. J Immunother 2005;28:220-8.  Back to cited text no. 31
    
32.
Salem ML, Diaz-Montero CM, El-Naggar SA, Chen Y, Moussa O, Cole DJ. The TLR3 agonist poly (I: C) targets CD8+T cells and augments their antigen-specific responses upon their adoptive transfer into naïve recipient mice. Vaccine 2009;27:549-57.  Back to cited text no. 32
    
33.
Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015;348:62-8.  Back to cited text no. 33
    
34.
Chatillon JF, Hamieh M, Bayeux F, Abasq C, Fauquembergue E, Drouet A, et al. Direct toll-like receptor 8 signaling increases the functional avidity of human CD8+T lymphocytes generated for adoptive T cell therapy strategies. Immun Inflamm Dis 2015;3:1-13.  Back to cited text no. 34
    


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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

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