Positive conversion of negative signaling of CTLA4 potentiates antitumor efficacy of adoptive T-cell therapy in murine tumor models

Blood - Tập 119 Số 24 - Trang 5678-5687 - 2012
Jae Hun Shin1, Hyung Bae Park2, Yu Mi Oh1, Dong Pyo Lim1, Ji Eun Lee1, Hae Hyun Seo3, Sang Jin Lee3, Hyeon Seok Eom2, In-Hoo Kim4, Seung Hoon Lee1, Kyungho Choi1
1Specific Organs Cancer Branch,
2Hematologic Malignancy Branch,
3Genitourinary Cancer Branch, and
4Molecular Imaging and Therapy branch, Research Institute National Cancer Center, Gyeonggi-do, Korea

Tóm tắt

AbstractCytotoxic T lymphocyte–associated antigen 4 (CTLA4) has been known to be a strong tolerance-inducing inhibitory receptor on T-cell surface. Systemic blocking of CTLA4 function with blocking antibodies has been regarded as an attractive strategy to enhance antitumor immunity. However, this strategy accompanies systemic autoimmune side effects that are sometimes problematic. Therefore, we developed a novel CTLA4 mutant that could be expressed in tumor antigen-specific T cells to enhance antitumor effect without systemic autoimmunity. This mutant, named CTLA4-CD28 chimera, consists of extracellular and transmembrane domains of CTLA4, linked with cytoplasmic CD28 domain. Overexpression of CTLA4-CD28 chimera in T cells delivered stimulatory signals rather than inhibitory signals of CTLA4 and significantly enhanced T-cell reactivity. Although this effect was observed in both CD4 and CD8 T cells, the effect on CD4 T cells was predominant. CTLA4-CD28 chimera gene modification of CD4 T cells significantly enhanced antitumor effect of unmodified CD8 T cells. Nonetheless, the gene modification of CD8 T cells along with CD4 T cells further maximized antitumor effect of T cells in 2 different murine tumor models. Thus, CTLA4-CD28 chimera gene modification of both tumor antigen-specific CD4 and CD8 T cells would be an ideal way of modulating CTLA4 function to enhance tumor-specific T-cell reactivity.

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Tài liệu tham khảo

Peggs, 2008, Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy., Immunol Rev, 224, 141, 10.1111/j.1600-065X.2008.00649.x

Waterhouse, 1995, Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4., Science, 270, 985, 10.1126/science.270.5238.985

Greenwald, 2001, CTLA-4 regulates induction of anergy in vivo., Immunity, 14, 145, 10.1016/S1074-7613(01)00097-8

Perrin, 1996, CTLA-4 blockade enhances clinical disease and cytokine production during experimental allergic encephalomyelitis., J Immunol, 157, 1333, 10.4049/jimmunol.157.4.1333

Lühder, 1998, Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulates the unfolding of autoimmune diabetes., J Exp Med, 187, 427, 10.1084/jem.187.3.427

Rabinovich, 2007, Immunosuppressive strategies that are mediated by tumor cells., Annu Rev Immunol, 25, 267, 10.1146/annurev.immunol.25.022106.141609

Leach, 1996, Enhancement of antitumor immunity by CTLA-4 blockade., Science, 271, 1734, 10.1126/science.271.5256.1734

Kwon, 1997, Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer., Proc Natl Acad Sci U S A, 94, 8099, 10.1073/pnas.94.15.8099

van Elsas, 1999, Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation., J Exp Med, 190, 355, 10.1084/jem.190.3.355

Agarwala, 2010, Current experience with CTLA4-blocking monoclonal antibodies for the treatment of solid tumors., J Immunother, 33, 557, 10.1097/CJI.0b013e3181dcd260

Robert, 2011, Ipilimumab plus dacarbazine for previously untreated metastatic melanoma., N Engl J Med, 364, 2517, 10.1056/NEJMoa1104621

Attia, 2005, Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4., J Clin Oncol, 23, 6043, 10.1200/JCO.2005.06.205

Beck, 2006, Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4., J Clin Oncol, 24, 2283, 10.1200/JCO.2005.04.5716

June, 2007, Adoptive T cell therapy for cancer in the clinic., J Clin Invest, 117, 1466, 10.1172/JCI32446

Heslop, 2010, Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients., Blood, 115, 925, 10.1182/blood-2009-08-239186

Dudley, 2002, Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes., Science, 298, 850, 10.1126/science.1076514

Dudley, 2008, Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens., J Clin Oncol, 26, 5233, 10.1200/JCO.2008.16.5449

Willimsky, 2005, Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance., Nature, 437, 141, 10.1038/nature03954

Kershaw, 2005, Supernatural T cells: genetic modification of T cells for cancer therapy., Nat Rev Immunol, 5, 928, 10.1038/nri1729

Morgan, 2006, Cancer regression in patients after transfer of genetically engineered lymphocytes., Science, 314, 126, 10.1126/science.1129003

Jena, 2010, Redirecting T-cell specificity by introducing a tumor-specific chimeric antigen receptor., Blood, 116, 1035, 10.1182/blood-2010-01-043737

Quintarelli, 2007, Co-expression of cytokine and suicide genes to enhance the activity and safety of tumor-specific cytotoxic T lymphocytes., Blood, 110, 2793, 10.1182/blood-2007-02-072843

Di Stasi, 2009, T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model., Blood, 113, 6392, 10.1182/blood-2009-03-209650

Dotti, 2005, Human cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis., Blood, 105, 4677, 10.1182/blood-2004-08-3337

Refaeli, 2002, Interferon gamma is required for activation-induced death of T lymphocytes., J Exp Med, 196, 999, 10.1084/jem.20020666

Linsley, 1991, Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation., J Exp Med, 173, 721, 10.1084/jem.173.3.721

Green, 1994, Absence of B7-dependent responses in CD28-deficient mice., Immunity, 1, 501, 10.1016/1074-7613(94)90092-2

Kane, 2001, Akt provides the CD28 costimulatory signal for up-regulation of IL-2 and IFN-gamma but not TH2 cytokines., Nat Immunol, 2, 37, 10.1038/83144

Krummel, 1995, CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation., J Exp Med, 182, 459, 10.1084/jem.182.2.459

Overwijk, 2003, Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells., J Exp Med, 198, 569, 10.1084/jem.20030590

Gattinoni, 2005, Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells., J Exp Med, 202, 907, 10.1084/jem.20050732

Antony, 2005, CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells., J Immunol, 174, 2591, 10.4049/jimmunol.174.5.2591

Carreno, 2000, CTLA-4 (CD152) can inhibit T cell activation by two different mechanisms depending on its level of cell surface expression., J Immunol, 165, 1352, 10.4049/jimmunol.165.3.1352

Masteller, 2000, Structural analysis of CTLA-4 function in vivo., J Immunol, 164, 5319, 10.4049/jimmunol.164.10.5319

Kowolik, 2006, CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells., Cancer Res, 66, 10995, 10.1158/0008-5472.CAN-06-0160

Hombach, 2001, Tumor-specific T cell activation by recombinant immunoreceptors: CD3 zeta signaling and CD28 costimulation are simultaneously required for efficient IL-2 secretion and can be integrated into one combined CD28/CD3 zeta signaling receptor molecule., J Immunol, 167, 6123, 10.4049/jimmunol.167.11.6123

Yin, 2003, Short cytoplasmic SDYMNM segment of CD28 is sufficient to convert CTLA-4 to a positive signaling receptor., J Leukoc Biol, 73, 178, 10.1189/jlb.0702365

Chambers, 1997, Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells., Immunity, 7, 885, 10.1016/S1074-7613(00)80406-9

Gattinoni, 2006, CTLA-4 dysregulation of self/tumor-reactive CD8+ T-cell function is CD4+ T-cell dependent., Blood, 108, 3818, 10.1182/blood-2006-07-034066

Chambers, 1998, Secondary but not primary T cell responses are enhanced in CTLA-4-deficient CD8+ T cells., Eur J Immunol, 28, 3137, 10.1002/(SICI)1521-4141(199810)28:10<3137::AID-IMMU3137>3.0.CO;2-X

Gajewski, 2001, Absence of CTLA-4 lowers the activation threshold of primed CD8+ TCR-transgenic T cells: lack of correlation with Src homology domain 2-containing protein tyrosine phosphatase., J Immunol, 166, 3900, 10.4049/jimmunol.166.6.3900

Gorelik, 2000, Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease., Immunity, 12, 171, 10.1016/S1074-7613(00)80170-3

Gorelik, 2001, Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells., Nat Med, 7, 1118, 10.1038/nm1001-1118

Foster, 2008, Antitumor activity of EBV-specific T lymphocytes transduced with a dominant negative TGF-beta receptor., J Immunother, 31, 500, 10.1097/CJI.0b013e318177092b

Muranski, 2009, Adoptive immunotherapy of cancer using CD4(+) T cells., Curr Opin Immunol, 21, 200, 10.1016/j.coi.2009.02.004

Hunder, 2008, Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1., N Engl J Med, 358, 2698, 10.1056/NEJMoa0800251

Shedlock, 2003, Requirement for CD4 T cell help in generating functional CD8 T cell memory., Science, 300, 337, 10.1126/science.1082305

Surman, 2000, Cutting edge: CD4+ T cell control of CD8+ T cell reactivity to a model tumor antigen., J Immunol, 164, 562, 10.4049/jimmunol.164.2.562

Bos, 2010, CD4+ T-cell help in the tumor milieu is required for recruitment and cytolytic function of CD8+ T lymphocytes., Cancer Res, 70, 8368, 10.1158/0008-5472.CAN-10-1322

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Blood

Tập 119 Số 24

5678-5687

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