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For: Liu JY, Zhang XS, Ding Y, Peng RQ, Cheng X, Zhang NH, Xia JC, Zeng YX. The changes of CD4+CD25+/CD4+ proportion in spleen of tumor-bearing BALB/c mice. J Transl Med 2005;3:5. [PMID: 15679891 PMCID: PMC549051 DOI: 10.1186/1479-5876-3-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2004] [Accepted: 01/28/2005] [Indexed: 12/27/2022] Open

For:	Liu JY, Zhang XS, Ding Y, Peng RQ, Cheng X, Zhang NH, Xia JC, Zeng YX. The changes of CD4+CD25+/CD4+ proportion in spleen of tumor-bearing BALB/c mice. J Transl Med 2005;3:5. [PMID: 15679891 PMCID: PMC549051 DOI: 10.1186/1479-5876-3-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2004] [Accepted: 01/28/2005] [Indexed: 12/27/2022] Open

Number

Cited by Other Article(s)

Wang W, Ye CH, Deng ZF, Wang JL, Zhang L, Bao L, Xu BH, Zhu H, Guo Y, Wen Z. CD4⁺CD25⁺ regulatory T cells decreased future liver remnant after associating liver partition and portal vein ligation for staged hepatectomy. World J Gastrointest Surg 2023;15:917-930. [PMID: 37342857 PMCID: PMC10277939 DOI: 10.4240/wjgs.v15.i5.917] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 12/22/2022] [Accepted: 04/04/2023] [Indexed: 05/26/2023] Open

Abstract

BACKGROUND

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is an innovative surgical approach for the treatment of massive hepatocellular carcinoma (HCC), the key to successful planned stage 2 ALPPS is future liver remnant (FLR) volume growth, but the exact mechanism has not been elucidated. The correlation between regulatory T cells (Tregs) and postoperative FLR regeneration has not been reported.

AIM

To investigate the effect of CD4+CD25+ Tregs on FLR regeneration after ALPPS.

METHODS

Clinical data and specimens were collected from 37 patients who developed massive HCC treated with ALPPS. Flow cytometry was performed to detect changes in the proportion of CD4+CD25+ Tregs to CD4+ T cells in peripheral blood before and after ALPPS. To analyze the relationship between peripheral blood CD4+CD25+ Treg proportion and clinicopathological information and liver volume.

RESULTS

The postoperative CD4+CD25+ Treg proportion in stage 1 ALPPS was negatively correlated with the amount of proliferation volume, proliferation rate, and kinetic growth rate (KGR) of the FLR after stage 1 ALPPS. Patients with low Treg proportion had significantly higher KGR than those with high Treg proportion (P = 0.006); patients with high Treg proportion had more severe postoperative pathological liver fibrosis than those with low Treg proportion (P = 0.043). The area under the receiver operating characteristic curve between the percentage of Tregs and proliferation volume, proliferation rate, and KGR were all greater than 0.70.

CONCLUSION

CD4+CD25+ Tregs in the peripheral blood of patients with massive HCC at stage 1 ALPPS were negatively correlated with indicators of FLR regeneration after stage 1 ALPPS and may influence the degree of fibrosis in patients' livers. Treg percentage was highly accurate in predicting the FLR regeneration after stage 1 ALPPS.

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Affiliation(s)

Wei Wang Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Chun-Hui Ye Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Zhen-Feng Deng Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Ji-Long Wang Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Ling Zhang Department of Radiology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Li Bao Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300000, China
Bang-Hao Xu Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Hai Zhu Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Ya Guo Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Zhang Wen Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China

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Yang Z, Rajendran S, Spires V, Poirson B, Gururajan M, Lin Z, Arbanas J, Krystek S, Loy J, Cheng Y, Carl S, Pace S, Wang Y, Mehl J, Xu S, Vasudevan K, Broz M, Lehman-McKeeman L, Morin P, Graziano RF. Target-Mediated Drug Disposition Affects the Pharmacokinetics of Interleukin-10 Fragment Crystallizable Fusion Proteins at Pharmacologically Active Doses. Drug Metab Dispos 2022;50:898-908. [PMID: 35545256 DOI: 10.1124/dmd.121.000799] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 04/25/2022] [Indexed: 11/22/2022] Open

Abstract

Fragment crystallizable (Fc) fusion is commonly used for extending the half-life of biotherapeutics such as cytokines. In this work, we studied the pharmacokinetics of Fc-fused interleukin-10 (IL-10) proteins that exhibited potent antitumor activity in mouse syngeneic tumor models. At pharmacologically active doses of ≥0.1 mg/kg, both mouse Fc-mouse IL-10 and human Fc-human IL-10, constructed as the C terminus of the Fc domain fused with IL-10 via a glycine-serine polypeptide linker, exhibited nonlinear pharmacokinetics after intravenous administration to mice at the doses of 0.05, 0.5, and 5 mg/kg. With a nominal dose ratio of 1:10:100; the ratio of the area under the curve for mouse Fc-mouse IL-10 and human Fc-human IL-10 was 1:181:1830 and 1:75:633, respectively. In contrast, recombinant mouse or human IL-10 proteins exhibited linear pharmacokinetics in mice. Compartmental analysis, using the Michaelis-Menten equation with the in vitro IL-10 receptor alpha binding affinity inputted as the Km, unified the pharmacokinetic data across the dose range. Additionally, nontarget-mediated clearance estimated for fusion proteins was ∼200-fold slower than that for cytokines, causing the manifestation of target-mediated drug disposition (TMDD) in the fusion protein pharmacokinetics. The experimental data generated with a mouse IL-10 receptor alpha-blocking antibody and a human Fc-human IL-10 mutant with a reduced receptor binding affinity showed significant improvements in pharmacokinetics, supporting TMDD as the cause of nonlinearity. Target expression and its effect on pharmacokinetics must be determined when considering using Fc as a half-life extension strategy, and pharmacokinetic evaluations need to be performed at a range of doses covering pharmacological activity. SIGNIFICANCE STATEMENT: Target-mediated drug disposition can manifest to affect the pharmacokinetics of a fragment crystallizable (Fc)-fused cytokine when the nontarget-mediated clearance of the cytokine is decreased due to neonatal Fc receptor-mediated recycling and molecular weight increases that reduce the renal clearance. The phenomenon was demonstrated with interleukin-10 Fc-fusion proteins in mice at pharmacologically active doses. Future drug designs using Fc as a half-life extension approach for cytokines need to consider target expression and its effect on pharmacokinetics at relevant doses.

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Affiliation(s)

Zheng Yang Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.)
Surendran Rajendran Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.)
Vanessa Spires Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.)
Brian Poirson Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.)
Murali Gururajan Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.)
Zheng Lin Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.)
Jaren Arbanas Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.)
Stanley Krystek Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.)
James Loy Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.)
Yuan Cheng Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.)
Stephen Carl Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.)
Samantha Pace Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.)
Yun Wang Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.)
John Mehl Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.)
Shihua Xu Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.)
Krishna Vasudevan Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.)
Miranda Broz Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.)
Lois Lehman-McKeeman Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.)
Paul Morin Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.)
Robert F Graziano Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.)

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Mosayebzadeh Roshan H, Abtahi-Eivary SH, Shojaee-Mend H, Mohammadzadeh A, Bahari Sani Z. The Effects of WW2/WW3 Domains of Smurf2 Molecule on CD4+CD25+/CD4+ Proportion in Spleen of 4T1 Tumor Bearing BALB/c Mice. IRANIAN BIOMEDICAL JOURNAL 2020;24:214-9. [PMID: 32306719 PMCID: PMC7275819 DOI: 10.29252/ibj.24.4.214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]

Zhou Y, Li Y, Lu J, Hong X, Xu L. MicroRNA‑30a controls the instability of inducible CD4+ Tregs through SOCS1. Mol Med Rep 2019;20:4303-4314. [PMID: 31545427 DOI: 10.3892/mmr.2019.10666] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 07/31/2019] [Indexed: 11/05/2022] Open

Abstract

Inducible regulatory T cells (iTregs) are an important subset of Tregs and play a role in the maintenance of peripheral tolerance, and the occurrence of a number of diseases, including tumors and autoimmune diseases. However, the instability of iTregs is a major obstacle for their potential application in clinical trials. The underlying mechanism of iTreg instability remains largely unknown. In the present study, the expression level of microRNA (miRNA/miR)‑30a in murine iTregs was evaluated using reverse transcription‑quantitative PCR. miR‑30a mimics and a miR‑negative control (NC) were transiently transfected into iTregs using Nucleofector technology. The effects of miR‑30a on the suppressive function of murine iTregs in vitro and in vivo were investigated using MTT, adoptive cell transfer (ACT) and flow cytometry assays, as well as a murine model of lung cancer. In the present study, it was identified that the expression level of miR‑30a was lower in murine iTregs in vitro compared with natural (n)Tregs. Furthermore, compared with miR‑NC, miR‑30a mimics impaired the suppressive function of murine iTregs on murine CD4+ T cell proliferation in vitro, which was accompanied by the altered expression of cytotoxic T lymphocyte‑associated antigen 4 and glucocorticoid induced tumor necrosis factor receptor, as well as transforming growth factor‑β and interleukin‑10. It was also observed that, compared with miR‑NC, miR‑30a mimics abrogated the suppressive effects of murine iTregs on murine CD8+ T cell function in vivo, producing an effective antitumor effect in mice bearing 3LL lung cancer cells in the ACT assay. From a mechanistic point, the expression level of suppressor of cytokine signaling 1, a putative target of miR‑30a, was elevated, altering the activation of the Akt and STAT1 pathway in the miR‑30a mimic transfected group compared with the miR‑NC group, reducing the suppressive function of murine iTregs. The present study identified a role for miR‑30a in the instability of iTregs and provided a novel insight into the development of therapeutic strategies for promoting T‑cell immunity via the regulation of iTreg instability by targeting specific miRNAs.

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Sharma P, Shin JB, Park BC, Lee JW, Byun SW, Jang NY, Kim YJ, Kim Y, Kim YK, Cho NH. Application of radially grown ZnO nanowires on poly-l-lactide microfibers complexed with a tumor antigen for cancer immunotherapy. NANOSCALE 2019;11:4591-4600. [PMID: 30809611 DOI: 10.1039/c8nr08704k] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]

Using the Spleen as an In Vivo Systemic Immune Barometer Alongside Osteosarcoma Disease Progression and Immunotherapy with α-PD-L1. Sarcoma 2018;2018:8694397. [PMID: 30651716 PMCID: PMC6311869 DOI: 10.1155/2018/8694397] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 10/15/2018] [Accepted: 10/29/2018] [Indexed: 12/22/2022] Open

Abstract

Indications for immunotherapies are still unclear, and there is a great need for real-time patient immune status monitoring. In this study, we confirmed that the local and systemic immune profiles of an orthotopic osteosarcoma model with or without luciferase transfection were statistically equivalent. Next, we used flow cytometry to describe systemic immune cell populations influenced by osteosarcoma disease progression. When compared to vehicle-inoculated sham mice, it was found that tumor-bearing mice had significant immunophenotype disturbances at approximately 11 weeks after inoculation (at which time 90% of primary tumor-bearing mice have fulminant pulmonary metastases). Percent populations of natural killer cells and T regulatory cells were increased in the spleens of tumor-bearing mice (p < 0.0083) compared to shams. Additionally, T lymphocytes from spleens of tumor-bearing mice showed increased Tim-3/PD-1 exhaustion status (p < 0.0083). There were also increases in the percent populations of myeloid cells and overall M1/M2 macrophage marker expression on tumor-bearing mice spleens versus controls (p < 0.00714). Finally, treatment with 20 μg α-PD-L1 decreased T-cell exhaustion back to sham status, with a corresponding increase in CTLA-4 expression on cytotoxic T cells in the majority of mice tested. Checkpoint inhibition also increased splenic monocyte maturation and returned macrophage M1/M2 marker expression back to sham status. These data suggest that cancer induces systemic immune dysregulation and that these changes may be elucidated and utilized for treatment purposes by sampling the systemic immune environment via the spleen. In addition, treatment with the checkpoint inhibitor α-PD-L1 may neutralize but not overcome the systemic immunological changes induced by a progressing malignancy.

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Wang B, Li B, Dai Z, Ren S, Bai M, Wang Z, Li Z, Lin S, Wang Z, Huang N, Yang P, Liu M, Min W, Ma H. Low-dose splenic radiation inhibits liver tumor development of rats through functional changes in CD4+CD25+Treg cells. Int J Biochem Cell Biol 2014;55:98-108. [PMID: 25168696 DOI: 10.1016/j.biocel.2014.08.014] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Revised: 07/27/2014] [Accepted: 08/17/2014] [Indexed: 02/07/2023]

Abstract

The increased number of CD4(+)CD25(+)Treg cells in tumor local and peripheral splenic tissues is related to the low immune function as well as to tumor recurrence and metastasis. Our pre-clinical studies showed that low-dose radiation (LDR) of the spleen in liver cancer patients significantly improves immune functions. However, the molecular mechanisms of such radiation remained ill defined. This study explores the role of CD4(+)CD25(+)Treg cells in radiation-induced immunomodulatory effects. Using the diethylnitrosamine (DEN)-induced rat liver tumor model and in vitro cell experiments, the percentage of CD4(+)CD25(+)Treg/CD4(+) cells in the blood and the expressions of Foxp3(+), IL-10, TGF-β, and cytotoxic T lymphocyte-associated antigen-4(CTLA-4) in spleen and liver tumors significantly decreased after LDR of the spleen in rats with liver cancer. The tumors became smaller than those in the non-radiated group, with both showing a parallel relation. Flow cytometry and MTT results revealed that LDR failed to inhibit CD4(+)CD25(+)Treg cell proliferation. Conversely, apoptosis was reduced and proliferation was stimulated. This process also changed CTLA-4 molecule expression on the surfaces of CD4(+)CD25(+)Treg cells and reduced their inhibitory function against CD4(+)CD25(-)T cell proliferation, and the suppression function of CD4(+)CD25(+)Treg cells was further weakened with the introduction of the CTLA-4 inhibitor. Findings demonstrate that the reduction of CTLA-4 expression on the CD4(+)CD25(+)Treg cell surface and the further inhibition of cell function may be considered as important regulators of LDR-induced immunomodulatory effects. This study provides experimental evidence to elucidate the immune enhancement induced by this process and presents a novel method for liver cancer immunotherapy.

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Affiliation(s)

Baofeng Wang Department of Oncology, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China.
Baohua Li Department of Surgery, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China.
Zhijun Dai Department of Oncology, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China.
Song Ren Department of Surgery, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China.
Minghua Bai Department of Oncology, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China.
Zhongwei Wang Department of Oncology, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China.
Zongfang Li Department of Surgery, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China.
Shuai Lin Department of Oncology, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China.
Zhidong Wang Department of Surgery, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China.
Na Huang Department of Surgery, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China.
Pengtao Yang Department of Oncology, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China.
Mengjie Liu Department of Oncology, The First Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710061, PR China.
Weili Min Department of Oncology, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China.
Hongbing Ma Department of Oncology, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China.

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Darrasse-Jèze G, Podsypanina K. How numbers, nature, and immune status of foxp3(+) regulatory T-cells shape the early immunological events in tumor development. Front Immunol 2013;4:292. [PMID: 24133490 PMCID: PMC3784046 DOI: 10.3389/fimmu.2013.00292] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Accepted: 09/05/2013] [Indexed: 12/21/2022] Open

Du Y, Chen X, Huang ZM, Ye XH, Niu Q. Increased Frequency of Foxp3+ Regulatory T Cells in Mice with Hepatocellular Carcinoma. Asian Pac J Cancer Prev 2012;13:3815-9. [DOI: 10.7314/apjcp.2012.13.8.3815] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open

Liu YL, Wang YD, Zhuang F, Xian SL, Fang JY, Su W, Zhang W. Immunosuppression effects of bone marrow mesenchymal stem cells on renal interstitial injury in rats with unilateral ureteral obstruction. Cell Immunol 2012;276:144-52. [PMID: 22632816 DOI: 10.1016/j.cellimm.2012.05.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2012] [Revised: 04/20/2012] [Accepted: 05/02/2012] [Indexed: 01/16/2023]

Ha TY. The role of regulatory T cells in cancer. Immune Netw 2009;9:209-35. [PMID: 20157609 PMCID: PMC2816955 DOI: 10.4110/in.2009.9.6.209] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2009] [Accepted: 11/11/2009] [Indexed: 12/18/2022] Open

Recent advances in multivalent self adjuvanting glycolipopeptide vaccine strategies against breast cancer. Arch Immunol Ther Exp (Warsz) 2009;57:409-23. [PMID: 19866342 DOI: 10.1007/s00005-009-0049-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2009] [Accepted: 06/19/2009] [Indexed: 12/27/2022]

Gao YF, Peng RQ, Li J, Ding Y, Zhang X, Wu XJ, Pan ZZ, Wan DS, Zeng YX, Zhang XS. The paradoxical patterns of expression of indoleamine 2,3-dioxygenase in colon cancer. J Transl Med 2009;7:71. [PMID: 19695096 PMCID: PMC2736158 DOI: 10.1186/1479-5876-7-71] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2009] [Accepted: 08/20/2009] [Indexed: 12/16/2022] Open

Abstract

Background

One of the putative mechanisms of tumor immune escape is based on the hypothesis that carcinomas actively create an immunosuppressed state via the expression of indoleamine 2,3-dioxygenase (IDO), both in the cancer cells and in the immune cells among the tumor-draining lymph nodes (TDLN). In an attempt to verify this hypothesis, the patterns of expression of IDO in the cancer cells and the immune cells among colon cancers were examined.

Methods

Seventy-one cases of pathologically-confirmed colon cancer tissues matched with adjacent non-cancerous tissues, lymph node metastases, and TDLN without metastases were collected at the Sun Yat-sen Cancer Center between January 2000 and December 2000. The expression of IDO and Bin1, an IDO regulator, was determined with an immunohistochemical assay. The association between IDO or Bin1 expression and TNM stages and the 5-year survival rate in colon cancer patients was analyzed.

Results

IDO and Bin1 were detected in the cytoplasm of cancer cells and normal epithelium. In primary colon cancer, the strong expression of IDO existed in 9/71 cases (12.7%), while the strong expression of Bin1 existed in 33/71 cases (46.5%). However, similar staining of IDO and Bin1 existed in the adjacent non-cancerous tissues. Among the 41 cases with primary colon tumor and lymph node metastases, decreased expression of IDO was documented in the lymph node metastases. Furthermore, among the TDLN without metastases, a higher density of IDO⁺cells was documented in 21/60 cases (35%). Both univariate and multivariate analyses revealed that the density of IDO⁺cells in TDLN was an independent prognostic factor. The patients with a higher density of IDO⁺cells in TDLN had a lower 5-year survival rate (37.5%) than the cells with a lower density (73.1%).

Conclusion

This study demonstrated paradoxical patterns of expression of IDO in colon cancer. The high density IDO⁺cells existed in TDLN and IDO was down-regulated in lymph nodes with metastases, implying that IDO in tumor and immune cells functions differently.

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Ménard C, Martin F, Apetoh L, Bouyer F, Ghiringhelli F. Cancer chemotherapy: not only a direct cytotoxic effect, but also an adjuvant for antitumor immunity. Cancer Immunol Immunother 2008;57:1579-87. [PMID: 18369619 PMCID: PMC11030219 DOI: 10.1007/s00262-008-0505-6] [Citation(s) in RCA: 119] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2008] [Accepted: 03/09/2008] [Indexed: 01/19/2023]

Lutsiak MEC, Tagaya Y, Adams AJ, Schlom J, Sabzevari H. Tumor-induced impairment of TCR signaling results in compromised functionality of tumor-infiltrating regulatory T cells. THE JOURNAL OF IMMUNOLOGY 2008;180:5871-81. [PMID: 18424706 DOI: 10.4049/jimmunol.180.9.5871] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]

Photodynamic therapy plus low-dose cyclophosphamide generates antitumor immunity in a mouse model. Proc Natl Acad Sci U S A 2008;105:5495-500. [PMID: 18378905 DOI: 10.1073/pnas.0709256105] [Citation(s) in RCA: 154] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open

Overcoming immune tolerance against multiple myeloma with lentiviral calnexin-engineered dendritic cells. Mol Ther 2007;16:269-79. [PMID: 18071334 DOI: 10.1038/sj.mt.6300369] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open

Larmonier N, Marron M, Zeng Y, Cantrell J, Romanoski A, Sepassi M, Thompson S, Chen X, Andreansky S, Katsanis E. Tumor-derived CD4(+)CD25(+) regulatory T cell suppression of dendritic cell function involves TGF-beta and IL-10. Cancer Immunol Immunother 2007;56:48-59. [PMID: 16612596 PMCID: PMC11030031 DOI: 10.1007/s00262-006-0160-8] [Citation(s) in RCA: 165] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2006] [Accepted: 03/13/2006] [Indexed: 12/20/2022]

Waldner M, Schimanski CC, Neurath MF. Colon cancer and the immune system: The role of tumor invading T cells. World J Gastroenterol 2006;12:7233-8. [PMID: 17143936 PMCID: PMC4087478 DOI: 10.3748/wjg.v12.i45.7233] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open

Beyer M, Schultze JL. Regulatory T cells in cancer. Blood 2006;108:804-11. [PMID: 16861339 DOI: 10.1182/blood-2006-02-002774] [Citation(s) in RCA: 542] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open