Molecular Fundamentals and Rationale for Immunotherapy in Metastatic Melanoma Treatment

Author(s): Mizue Terai, Takami Sato.

Journal Name: Clinical Cancer Drugs

Volume 2 , Issue 1 , 2015

Submit Manuscript
Submit Proposal

Graphical Abstract:


Clinical application of immune checkpoint blockades has dramatically changed the landscape of cancer immunotherapy, especially in the field of metastatic melanoma. For the first time in the history of treatment of melanoma, immunotherapies using immune checkpoint blockades such as anti-Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) and Program Death-1 (PD-1) antibodies have consistently shown regression of metastatic tumors with survival benefit. However, the treatment of metastatic melanoma with immune checkpoint blockades has also brought new scientific and clinical challenges to treating physicians and clinical investigators. Such new challenges include: (1) how should we manage/ minimize serious immune-related adverse events without sacrificing anti-cancer effects?, (2) how should we choose one immune checkpoint blockade over others and in what sequence?, (3) how should we combine the immune checkpoint blockade with other cancer treatments such as chemotherapy, radiotherapy and signal blockades?, and (4) how can we predict clinical response with new immunological agents? In this review, we provide an overview of the molecular basis of new immunotherapies for metastatic melanoma and discussed potential strategies to improve the treatment outcomes using immune checkpoint blockades alone or in combination with various therapeutic modalities.

Keywords: Melanoma, immunotherapy, CTLA-4, PD-1, PD-L1.

Oble DA, Loewe R, Yu P, Mihm MC Jr. Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human melanoma. Cancer Immun 2009; 9: 3.
Seliger B, Maeurer MJ, Ferrone S. Antigen-processing machinery breakdown and tumor growth. Immunol Today 2000; 21(9): 455-64.
Garcia-Lora A, Algarra I, Garrido F. MHC class I antigens, immune surveillance, and tumor immune escape. J Cell Physiol 2003; 195(3): 346-55.
Lopez-Nevot MA, Garcia E, Romero C, Oliva MR, Serrano S, Garrido F. Phenotypic and genetic analysis of HLA class I and HLA-DR antigen expression on human melanomas. Exp Clin Immunogenet 1988; 5(4): 203-12.
Wetzler M, McElwain BK, Stewart CC, Blumenson L, Mortazavi A, Ford LA. HLA-DR antigen-negative acute myeloid leukemia. Leukemia 2003; 17(4): 707-15.
Chen JJ, Lin YC, Yao PL, Yuan A, Chen HY, Shun CT. Tumor-associated macrophages: the double-edged sword in cancer progression. J Clin Oncol 2005; 23(5): 953-64.
Solinas G, Germano G, Mantovani A, Allavena P. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 2009; 86(5): 1065-73.
Mahipal A, Terai M, Berd D, Chervoneva I, Patel K, Mastrangelo MJ. Tumor-derived interleukin-10 as a prognostic factor in stage III patients undergoing adjuvant treatment with an autologous melanoma cell vaccine. Cancer Immunol Immunother 2011; 60(7): 1039-45.
Sato T, Terai M, Tamura Y, Alexeev V, Mastrangelo MJ, Selvan SR. Interleukin 10 in the tumor microenvironment: a target for anticancer immunotherapy. Immunol Res 2011; 51(2-3): 170-82.
Roberts AB, Wakefield LM. The two faces of transforming growth factor beta in carcinogenesis. Proc Natl Acad Sci USA 2003; 100(15): 8621-3.
Ruiter DJ, Bergman W, Welvaart K, Scheffer E, van Vloten WA, Russo C. Immunohistochemical analysis of malignant melanomas and nevocellular nevi with monoclonal antibodies to distinct monomorphic determinants of HLA antigens. Cancer Res 1984; 44(9): 3930-5.
D’Alessandro G, Zardawi I, Grace J, McCarthy WH, Hersey P. Immunohistological evaluation of MHC class I and II antigen expression on nevi and melanoma: relation to biology of melanoma. Pathology 1987; 19(4): 339-46.
Bui HH, Sidney J, Peters B, Sathiamurthy M, Sinichi A, Purton KA. Automated generation and evaluation of specific MHC binding predictive tools: ARB matrix applications. Immunogenetics 2005; 57(5): 304-14.
Lundegaard C, Lund O, Nielsen M. Prediction of epitopes using neural network based methods. J Immunol Methods 2011; 374(1-2): 26-34.
Brown SD, Warren RL, Gibb EA, Martin SD, Spinelli JJ, Nelson BH. Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res 2014; 24(5): 743-50.
Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8): 711-23.
Lee PP, Yee C, Savage PA, Fong L, Brockstedt D, Weber JS. Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat Med 1999; 5(6): 677-85.
Zippelius A, Batard P, Rubio-Godoy V, Bioley G, Lienard D, Lejeune F. Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res 2004; 64(8): 2865-73.
Wang F, Bade E, Kuniyoshi C, Spears L, Jeffery G, Marty V. Phase I trial of a MART-1 peptide vaccine with incomplete Freund’s adjuvant for resected high-risk melanoma. Clin Cancer Res 1999; 5(10): 2756-65.
Yuan J, Ku GY, Gallardo HF, Orlandi F, Manukian G, Rasalan TS. Safety and immunogenicity of a human and mouse gp100 DNA vaccine in a phase I trial of patients with melanoma. Cancer Immun 2009; 9: 5.
Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006; 314(5796): 126-9.
Benlalam H, Vignard V, Khammari A, Bonnin A, Godet Y, Pandolfino MC. Infusion of Melan-A/Mart-1 specific tumor-infiltrating lymphocytes enhanced relapse-free survival of melanoma patients. Cancer Immunol Immunother 2007; 56(4): 515-26.
Phan GQ, Rosenberg SA. Adoptive cell transfer for patients with metastatic melanoma: the potential and promise of cancer immunotherapy. Cancer Contr 2013; 20(4): 289-97.
Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Sakaguchi K, Appella E. Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection. Proc Natl Acad Sci USA 1994; 91(14): 6458-62.
Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Rivoltini L, Topalian SL. Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc Natl Acad Sci USA 1994; 91(9): 3515-9.
Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 2014; 344(6184): 641-5.
Lu YC, Yao X, Li YF, El-Gamil M, Dudley ME, Yang JC. Mutated PPP1R3B is recognized by T cells used to treat a melanoma patient who experienced a durable complete tumor regression. J Immunol 2013; 190(12): 6034-42.
Lu YC, Yao X, Crystal JS, Li YF, El-Gamil M, Gross C. Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions. Clin Cancer Res 2014; 20(13): 3401-10.
van der Merwe PA, Davis SJ. Molecular interactions mediating T cell antigen recognition. Annu Rev Immunol 2003; 21: 659-84.
Paust S, Lu L, McCarty N, Cantor H. Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease. Proc Natl Acad Sci USA 2004; 101(28): 10398-403.
Harper K, Balzano C, Rouvier E, Mattei MG, Luciani MF, Golstein P. CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location. J Immunol 1991; 147(3): 1037-44.
Linsley PS, Brady W, Grosmaire L, Aruffo A, Damle NK, Ledbetter JA. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med 1991; 173(3): 721-30.
Linsley PS, Clark EA, Ledbetter JA. T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1. Proc Natl Acad Sci USA 1990; 87(13): 5031-5.
Collins AV, Brodie DW, Gilbert RJ, Iaboni A, Manso-Sancho R, Walse B, et al. The interaction properties of costimulatory molecules revisited. Immunity 2002; 17(2): 201-10.
Stamper CC, Zhang Y, Tobin JF, Erbe DV, Ikemizu S, Davis SJ. Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses. Nature 2001; 410(6828): 608-11.
Linsley PS, Greene JL, Tan P, Bradshaw J, Ledbetter JA, Anasetti C. Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J Exp Med 1992; 176(6): 1595-604.
Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 2011; 332(6029): 600-3.
Marengere LE, Waterhouse P, Duncan GS, Mittrucker HW, Feng GS, Mak TW. Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4. Science 1996; 272(5265): 1170-3.
Chuang E, Fisher TS, Morgan RW, Robbins MD, Duerr JM, Vander Heiden MG. The CD28 and CTLA-4 receptors associate with the serine/threonine phosphatase PP2A. Immunity 2000; 13(3): 313-22.
Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005; 25(21): 9543-53.
Chuang E, Alegre ML, Duckett CS, Noel PJ, Vander Heiden MG, Thompson CB. Interaction of CTLA-4 with the clathrin-associated protein AP50 results in ligand-independent endocytosis that limits cell surface expression. J Immunol 1997; 159(1): 144-51.
Linsley PS, Bradshaw J, Greene J, Peach R, Bennett KL, Mittler RS. Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. Immunity 1996; 4(6): 535-43.
Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 1995; 270(5238): 985-8.
Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995; 3(5): 541-7.
Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996; 271(5256): 1734-6.
Pedicord VA, Montalvo W, Leiner IM, Allison JP. Single dose of anti-CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance. Proc Natl Acad Sci USA 2011; 108(1): 266-71.
Hurwitz AA, Yu TF, Leach DR, Allison JP. CTLA-4 blockade synergizes with tumor-derived granulocyte-macrophage colony-stimulating factor for treatment of an experimental mammary carcinoma. Proc Natl Acad Sci USA 1998; 95(17): 10067-71.
Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG. A new member of the immunoglobulin superfamily--CTLA-4. Nature 1987; 328(6127): 267-70.
Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z. CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008; 322(5899): 271-5.
Kuiper HM, Brouwer M, Linsley PS, van Lier RA. Activated T cells can induce high levels of CTLA-4 expression on B cells. J Immunol 1995; 155(4): 1776-83.
Contardi E, Palmisano GL, Tazzari PL, Martelli AM, Fala F, Fabbi M. CTLA-4 is constitutively expressed on tumor cells and can trigger apoptosis upon ligand interaction. Int J Cancer 2005; 117(4): 538-50.
Chan DV, Gibson HM, Aufiero BM, Wilson AJ, Hafner MS, Mi QS. Differential CTLA-4 expression in human CD4+ versus CD8+ T cells is associated with increased NFAT1 and inhibition of CD4+ proliferation. Genes Immun 2014; 15(1): 25-32.
Jago CB, Yates J, Camara NO, Lechler RI, Lombardi G. Differential expression of CTLA-4 among T cell subsets. Clin Exp Immunol 2004; 136(3): 463-71.
Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 2003; 100(14): 8372-7.
Chen H, Liakou CI, Kamat A, Pettaway C, Ward JF, Tang DN. Anti-CTLA-4 therapy results in higher CD4+ICOShi T cell frequency and IFN-gamma levels in both nonmalignant and malignant prostate tissues. Proc Natl Acad Sci USA 2009; 106(8): 2729-34.
Weber JS, Hamid O, Chasalow SD, Wu DY, Parker SM, Galbraith S. Ipilimumab increases activated T cells and enhances humoral immunity in patients with advanced melanoma. J Immunother 2012; 35(1): 89-97.
Robert C, Thomas L, Bondarenko I, O’Day S. M DJ, Garbe C. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364(26): 2517-26.
Pico de Coana Y, Poschke I, Gentilcore G, Mao Y, Nystrom M, Hansson J. Ipilimumab treatment results in an early decrease in the frequency of circulating granulocytic myeloid-derived suppressor cells as well as their Arginase1 production. Cancer Immunol Res 2013; 1(3): 158-62.
Khattak MA, Fisher R, Hughes P, Gore M, Larkin J. Ipilimumab activity in advanced uveal melanoma. Melanoma Res 2013; 23(1): 79-81.
Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992; 11(11): 3887-95.
Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett 2004; 574(1-3): 37-41.
Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 1996; 8(5): 765-72.
Cheng X, Veverka V, Radhakrishnan A, Waters LC, Muskett FW, Morgan SH. Structure and interactions of the human programmed cell death 1 receptor. J Biol Chem 2013; 288(17): 11771-85.
Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 2007; 27(1): 111-22.
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008; 26: 677-704.
Norris S, Coleman A, Kuri-Cervantes L, Bower M, Nelson M, Goodier MR. PD-1 expression on natural killer cells and CD8(+) T cells during chronic HIV-1 infection. Viral Immunol 2012; 25(4): 329-32.
Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol 2004; 173(2): 945-54.
Kinter AL, Godbout EJ, McNally JP, Sereti I, Roby GA, O’Shea MA. The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol 2008; 181(10): 6738-46.
Cho HY, Lee SW, Seo SK, Choi IW, Choi I, Lee SW. Interferon-sensitive response element (ISRE) is mainly responsible for IFN-alpha-induced upregulation of programmed death-1 (PD-1) in macrophages. Biochim Biophys Acta 2008; 1779(12): 811-9.
Terawaki S, Chikuma S, Shibayama S, Hayashi T, Yoshida T, Okazaki T. IFN-alpha directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity. J Immunol 2011; 186(5): 2772-9.
Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 2009; 114(8): 1537-44.
Inozume T, Hanada K, Wang QJ, Ahmadzadeh M, Wunderlich JR, Rosenberg SA. Selection of CD8+PD-1+ lymphocytes in fresh human melanomas enriches for tumor-reactive T cells. J Immunother 2010; 33(9): 956-64.
Rodig N, Ryan T, Allen JA, Pang H, Grabie N, Chernova T. Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis. Eur J Immunol 2003; 33(11): 3117-26.
Yang W, Li H, Chen PW, Alizadeh H, He Y, Hogan RN. PD-L1 expression on human ocular cells and its possible role in regulating immune-mediated ocular inflammation. Invest Ophthalmol Vis Sci 2009; 50(1): 273-80.
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002; 8(8): 793-800.
Wolfle SJ, Strebovsky J, Bartz H, Sahr A, Arnold C, Kaiser C. PD-L1 expression on tolerogenic APCs is controlled by STAT-3. Eur J Immunol 2011; 41(2): 413-24.
Liang SC, Latchman YE, Buhlmann JE, Tomczak MF, Horwitz BH, Freeman GJ. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol 2003; 33(10): 2706-16.
Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 2009; 206(13): 3015-29.
Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M, Saito T. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med 2012; 209(6): 1201-17.
Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999; 11(2): 141-51.
Ansari MJ, Salama AD, Chitnis T, Smith RN, Yagita H, Akiba H. The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med 2003; 198(1): 63-9.
Gadiot J, Hooijkaas AI, Kaiser AD, van Tinteren H, van Boven H, Blank C. Overall survival and PD-L1 expression in metastasized malignant melanoma. Cancer 2011; 117(10): 2192-201.
Errico A. Genetics: SMARCA4 mutated in SCCOHT. Nat Rev Clin Oncol 2014; 11(6): 302.
Baixeras E, Huard B, Miossec C, Jitsukawa S, Martin M, Hercend T. Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens. J Exp Med 1992; 176(2): 327-37.
Kisielow M, Kisielow J, Capoferri-Sollami G, Karjalainen K. Expression of lymphocyte activation gene 3 (LAG-3) on B cells is induced by T cells. Eur J Immunol 2005; 35(7): 2081-8.
Camisaschi C, Casati C, Rini F, Perego M, De Filippo A, Triebel F. LAG-3 expression defines a subset of CD4(+)CD25(high)Foxp3(+) regulatory T cells that are expanded at tumor sites. J Immunol 2010; 184(11): 6545-51.
Miyazaki T, Dierich A, Benoist C, Mathis D. Independent modes of natural killing distinguished in mice lacking Lag3. Science 1996; 272(5260): 405-8.
Huard B, Prigent P, Tournier M, Bruniquel D, Triebel F. CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins. Eur J Immunol 1995; 25(9): 2718-21.
Huard B, Mastrangeli R, Prigent P, Bruniquel D, Donini S, El-Tayar N. Characterization of the major histocompatibility complex class II binding site on LAG-3 protein. Proc Natl Acad Sci USA 1997; 94(11): 5744-9.
Hemon P, Jean-Louis F, Ramgolam K, Brignone C, Viguier M, Bachelez H. MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis. J Immunol 2011; 186(9): 5173-83.
Camisaschi C, De Filippo A, Beretta V, Vergani B, Villa A, Vergani E. Alternative activation of human plasmacytoid DCs in vitro and in melanoma lesions: involvement of LAG-3. J Invest Dermatol 2014; 134(7): 1893-902.
Goding SR, Wilson KA, Xie Y, Harris KM, Baxi A, Akpinarli A. Restoring immune function of tumor-specific CD4+ T cells during recurrence of melanoma. J Immunol 2013; 190(9): 4899-909.
Zhou Z, Kim S, Hurtado J, Lee ZH, Kim KK, Pollok KE. Characterization of human homologue of 4-1BB and its ligand. Immunol Lett 1995; 45(1-2): 67-73.
Alderson MR, Smith CA, Tough TW, Davis-Smith T, Armitage RJ, Falk B. Molecular and biological characterization of human 4-1BB and its ligand. Eur J Immunol 1994; 24(9): 2219-27.
Vinay DS, Kwon BS. Immunotherapy of cancer with 4-1BB. Mol Cancer Ther 2012; 11(5): 1062-70.
Wang C, Lin GH, McPherson AJ, Watts TH. Immune regulation by 4-1BB and 4-1BBL: complexities and challenges. Immunol Rev 2009; 229(1): 192-215.
Watts TH. TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol 2005; 23: 23-68.
Shuford WW, Klussman K, Tritchler DD, Loo DT, Chalupny J, Siadak AW. 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. J Exp Med 1997; 186(1): 47-55.
Kroon HM, Li Q, Teitz-Tennenbaum S, Whitfield JR, Noone AM, Chang AE. 4-1BB costimulation of effector T cells for adoptive immunotherapy of cancer: involvement of Bcl gene family members. J Immunother 2007; 30(4): 406-16.
Kwajah MMS, Schwarz H. CD137 ligand signaling induces human monocyte to dendritic cell differentiation. Eur J Immunol 2010; 40(7): 1938-49.
Teijeira A, Palazon A, Garasa S, Marre D, Auba C, Rogel A. CD137 on inflamed lymphatic endothelial cells enhances CCL21-guided migration of dendritic cells. FASEB J 2012; 26(8): 3380-92.
Laderach D, Wesa A, Galy A. 4-1BB-ligand is regulated on human dendritic cells and induces the production of IL-12. Cell Immunol 2003; 226(1): 37-44.
Kwon BS, Hurtado JC, Lee ZH, Kwack KB, Seo SK, Choi BK. Immune responses in 4-1BB (CD137)-deficient mice. J Immunol 2002; 168(11): 5483-90.
Li B, Lin J, Vanroey M, Jure-Kunkel M, Jooss K. Established B16 tumors are rejected following treatment with GM-CSF-secreting tumor cell immunotherapy in combination with anti-4-1BB mAb. Clin Immunol 2007; 125(1): 76-87.
Curran MA, Geiger TL, Montalvo W, Kim M, Reiner SL, Al-Shamkhani A. Systemic 4-1BB activation induces a novel T cell phenotype driven by high expression of Eomesodermin. J Exp Med 2013; 210(4): 743-55.
Melero I, Johnston JV, Shufford WW, Mittler RS, Chen L. NK1.1 cells express 4-1BB (CDw137) costimulatory molecule and are required for tumor immunity elicited by anti-4-1BB monoclonal antibodies. Cell Immunol 1998; 190(2): 167-72.
Curran MA, Kim M, Montalvo W, Al-Shamkhani A, Allison JP. Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine production. PLoS One 2011; 6(4): e19499.
Hendriks J, Gravestein LA, Tesselaar K, van Lier RA, Schumacher TN, Borst J. CD27 is required for generation and long-term maintenance of T cell immunity. Nat Immunol 2000; 1(5): 433-40.
Hamann D, Baars PA, Rep MH, Hooibrink B, Kerkhof-Garde SR, Klein MR. Phenotypic and functional separation of memory and effector human CD8+ T cells. J Exp Med 1997; 186(9): 1407-18.
Hendriks J, Xiao Y, Borst J. CD27 promotes survival of activated T cells and complements CD28 in generation and establishment of the effector T cell pool. J Exp Med 2003; 198(9): 1369-80.
Borst J, Hendriks J, Xiao Y. CD27 and CD70 in T cell and B cell activation. Curr Opin Immunol 2005; 17(3): 275-81.
Brown GR, Meek K, Nishioka Y, Thiele DL. CD27-CD27 ligand/CD70 interactions enhance alloantigen-induced proliferation and cytolytic activity in CD8+ T lymphocytes. J Immunol 1995; 154(8): 3686-95.
Yamada S, Shinozaki K, Agematsu K. Involvement of CD27/CD70 interactions in antigen-specific cytotoxic T-lymphocyte (CTL) activity by perforin-mediated cytotoxicity. Clin Exp Immunol 2002; 130(3): 424-30.
Soares H, Waechter H, Glaichenhaus N, Mougneau E, Yagita H, Mizenina O. A subset of dendritic cells induces CD4+ T cells to produce IFN-gamma by an IL-12-independent but CD70-dependent mechanism in vivo. J Exp Med 2007; 204(5): 1095-106.
De Colvenaer V, Taveirne S, Delforche M, De Smedt M, Vandekerckhove B, Taghon T, et al. CD27-deficient mice show normal NK-cell differentiation but impaired function upon stimulation. Immunol Cell Biol 2011; 89(7): 803-11.
Roberts DJ, Franklin NA, Kingeter LM, Yagita H, Tutt AL, Glennie MJ. Control of established melanoma by CD27 stimulation is associated with enhanced effector function and persistence, and reduced PD-1 expression of tumor infiltrating CD8(+) T cells. J Immunother 2010; 33(8): 769-79.
Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. J Immunother Cancer 2014; 2: 3.
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369(2): 122-33.
Sznol M, Kluger HM, Callahan MK, Postow MA, Gordon RA, Segal NH. editors. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). ASCO Annual Meeting Proceedings; 2014.
Prendergast GC. Immune escape as a fundamental trait of cancer: focus on IDO. Oncogene 2008; 27(28): 3889-900.
Fallarino F, Orabona C, Vacca C, Bianchi R, Gizzi S, Asselin-Paturel C. Ligand and cytokine dependence of the immunosuppressive pathway of tryptophan catabolism in plasmacytoid dendritic cells. Int Immunol 2005; 17(11): 1429-38.
Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med 2013; 5(200): 200ra116.
Lampen MH, van Hall T. Strategies to counteract MHC-I defects in tumors. Curr Opin Immunol 2011; 23(2): 293-8.
Kim K, Skora AD, Li Z, Liu Q, Tam AJ, Blosser RL. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci USA 2014; 111(32): 11774-9.
Demaria S, Kawashima N, Yang AM, Devitt ML, Babb JS, Allison JP. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res 2005; 11(2 Pt 1): 728-34.
Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 2012; 366(10): 925-31.
Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick J. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys 2013; 86(2): 343-9.
Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 2014; 124(2): 687-95.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2015
Page: [4 - 15]
Pages: 12
DOI: 10.2174/2212697X02666150203212041

Article Metrics

PDF: 25