Cancer immunotherapy with tumor-directed antibodies has generally been very successful, while T-cell immunotherapy has been less effective. Some lymphoid malignancies can be cured with immunochemotherapy but nevertheless many patients relapse or progress in spite of maximal therapy. Both solid tumors and lymphoid malignancies develop mechanisms in order to escape destruction by the intact immune system. One such mechanism is mediated through immune checkpoints. PD-1 (programmed cell death protein-1, which is expressed on activated T and B cells, natural killer cells and myeloid cells, is one of those checkpoints. This review focuses on the effect of PD-1 activation on lymphoid malignancies and its role as a therapeutic target. © 2014 S. Karger AG, Basel

1.
Aruffo A, Seed B: Molecular cloning of a CD28 CDNA by a high-efficiency COS cell expression system. Proc Natl Acad Sci USA 1987;84:8573-8577.
[PubMed]
2.
Larsen CP, Ritchie SC, Hendrix R, Linsley PS, Hathcock KS, Hodes RJ, Lowry RP, Pearson TC: Regulation of immunostimulatory function and costimulatory molecule (B7-1 and B7-2) expression on murine dendritic cells. J Immunol 1994;152:5208-5219.
[PubMed]
3.
Vigano S, Perreau M, Pantaleo G, Harari A: Positive and negative regulation of cellular immune responses in physiologic conditions and diseases. Clin Dev Immunol 2012;2012:485781.
[PubMed]
4.
Walker LS, Sansom DM: The emerging role of CTLA4 as a cell-extrinsic regulator of T-cell responses. Nat Rev Immunol 2011;11:852-863.
[PubMed]
5.
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-723.
[PubMed]
6.
Wakamatsu E, Mathis D, Benoist C: Convergent and divergent effects of costimulatory molecules in conventional and regulatory CD4+ T cells. Proc Natl Acad Sci USA 2013;110:1023-1028.
[PubMed]
7.
Cheng X, Veverka V, Radhakrishnan A, Waters LC, Muskett FW, Morgan SH, Huo J, Yu C, Evans EJ, Leslie AJ, Griffiths M, Stubberfield C, Griffin R, Henry AJ, Jansson A, Ladbury JE, Ikemizu S, Carr MD, Davis SJ: Structure and interactions of the human programmed cell death 1 receptor. J Biol Chem 2013;288:11771-11785.
[PubMed]
8.
Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, Honjo T: Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 1996;8:765-772.
[PubMed]
9.
Vivier E, Daeron M: Immunoreceptor tyrosine-based inhibition motifs. Immunol Today 1997;18:286-291.
[PubMed]
10.
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;11:3887-3895.
[PubMed]
11.
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;173:945-954.
[PubMed]
12.
Nishimura H, Honjo T: PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol 2001;22:265-268.
[PubMed]
13.
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T: Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000;192:1027-1034.
[PubMed]
14.
Greaves P, Gribben JG: The role of B7 family molecules in hematologic malignancy. Blood 2013;121:734-744.
[PubMed]
15.
Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ: PD-L2 is a second ligand for PD-1 and inhibits T-cell activation. Nat Immunol 2001;2:261-268.
[PubMed]
16.
Quezada SA, Peggs KS: Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer. Br J Cancer 2013;108:1560-1565.
[PubMed]
17.
Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R: Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006;439:682-687.
[PubMed]
18.
Petrovas C, Casazza JP, Brenchley JM, Price DA, Gostick E, Adams WC, Precopio ML, Schacker T, Roederer M, Douek DC, Koup RA: PD-1 is a regulator of virus-specific CD8+ T-cell survival in HIV infection. J Exp Med 2006;203:2281-2292.
[PubMed]
19.
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;11:141-151.
[PubMed]
20.
Latchman YE, Liang SC, Wu Y, Chernova T, Sobel RA, Klemm M, Kuchroo VK, Freeman GJ, Sharpe AH: PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells. Proc Natl Acad Sci USA 2004;101:10691-10696.
[PubMed]
21.
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L: Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002;8:793-800.
[PubMed]
22.
Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, Krejci KG, Lobo JR, Sengupta S, Chen L, Zincke H, Blute ML, Strome SE, Leibovich BC, Kwon ED: Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci USA 2004;101:17174-17179.
[PubMed]
23.
Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N, Honjo T, Fujii S: Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA 2007;104:3360-3365.
[PubMed]
24.
Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, Okazaki T, Tokura Y: Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 2010;116:1757-1766.
[PubMed]
25.
Sfanos KS, Bruno TC, Meeker AK, De Marzo AM, Isaacs WB, Drake CG: Human prostate-infiltrating CD8+ T lymphocytes are oligoclonal and PD-1+. Prostate 2009;69:1694-1703.
[PubMed]
26.
Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, Rosenberg SA: Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 2009;114:1537-1544.
[PubMed]
27.
Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P, Mottram P, Krzysiek R, Knutson KL, Daniel B, Zimmermann MC, David O, Burow M, Gordon A, Dhurandhar N, Myers L, Berggren R, Hemminki A, Alvarez RD, Emilie D, Curiel DT, Chen L, Zou W: Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 2003;9:562-567.
[PubMed]
28.
Khalili JS, Liu S, Rodriguez-Cruz TG, Whittington M, Wardell S, Liu C, Zhang M, Cooper ZA, Frederick DT, Li Y, Joseph RW, Bernatchez C, Ekmekcioglu S, Grimm E, Radvanyi LG, Davis RE, Davies MA, Wargo JA, Hwu P, Lizee G: Oncogenic BRAF (V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. Clin Cancer Res 2012;18:5329-5340.
[PubMed]
29.
Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252-264.
[PubMed]
30.
Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM: Safety and activity of anti PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455-2465.
[PubMed]
31.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-2454.
[PubMed]
32.
Sznol M, Kluger HM, Hodi FS, McDermott DF, Carvajal RD, Lawrence DP, Topalian SL, Atkins MB, Powderly JD, Sharfman WH: Survival and long-term follow-up of safety and response in patients with advanced melanoma in a phase I trial of nivolumab (anti-PD-1; BMS-936558; ONO-4538). J Clin Oncol 2013;31:549S.
33.
McDermott DF, Drake CG, Sznol M, Choueiri TK, Powderly J, Smith DC, Wigginton J, McDonald D, Kollia G, Gupta AK, Atkins MB: Clinical activity and safety of anti-PD-1 (BMS-936558, MDX-1106) in patients with previously treated metastatic renal cell carcinoma. J Clin Oncol 2012;30, abstract 4505.
34.
Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL, Gilson MM, Wang C, Selby M, Taube JM, Anders R, Chen L, Korman AJ, Pardoll DM, Lowy I, Topalian SL: Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010;28:3167-3175.
[PubMed]
35.
Patnaik A, Kang SP, Tolcher AW, Rasco DW, Papadopoulos KP, Beeram M, Drengler R, Chen C, Smith L, Perez C, Gergich K, Lehnert M: Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. ASCO Meeting Abstracts, 2012, vol 30, abstract 2512.
36.
Kozako T, Yoshimitsu M, Fujiwara H, Masamoto I, Horai S, White Y, Akimoto M, Suzuki S, Matsushita K, Uozumi K, Tei C, Arima N: PD-1/PD-L1 expression in human T-cell leukemia virus type 1 carriers and adult T-cell leukemia/lymphoma patients. Leukemia 2009;23:375-382.
[PubMed]
37.
Xerri L, Chetaille B, Serriari N, Attias C, Guillaume Y, Arnoulet C, Olive D: Programmed death 1 is a marker of angioimmunoblastic T-cell lymphoma and B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia. Hum Pathol 2008;39:1050-1058.
[PubMed]
38.
Andorsky DJ, Yamada RE, Said J, Pinkus GS, Betting DJ, Timmerman JM: Programmed death ligand 1 is expressed by non-Hodgkin lymphomas and inhibits the activity of tumor-associated T cells. Clin Cancer Res 2011;17:4232-4244.
[PubMed]
39.
Brusa D, Serra S, Coscia M, Rossi D, D'Arena G, Laurenti L, Jaksic O, Fedele G, Inghirami G, Gaidano G, Malavasi F, Deaglio S: The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia. Haematologica 2013;98:953-963.
[PubMed]
40.
Ramsay AG, Clear AJ, Fatah R, Gribben JG: Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer. Blood 2012;120:1412-1421.
[PubMed]
41.
Richendollar BG, Pohlman B, Elson P, Hsi ED: Follicular programmed death-1-positive lymphocytes in the tumor microenvironment are an independent prognostic factor in follicular lymphoma. Hum Pathol 2011;42:552-557.
[PubMed]
42.
Wahlin BE, Aggarwal M, Montes-Moreno S, Gonzalez LF, Roncador G, Sanchez-Verde L, Christensson B, Sander B, Kimby E: A unifying microenvironment model in follicular lymphoma: outcome is predicted by programmed death-1-positive, regulatory, cytotoxic, and helper T cells and macrophages. Clin Cancer Res 2010;16:637-650.
[PubMed]
43.
Carreras J, Lopez-Guillermo A, Roncador G, Villamor N, Colomo L, Martinez A, Hamoudi R, Howat WJ, Montserrat E, Campo E: High numbers of tumor-infiltrating programmed cell death-1-positive regulatory lymphocytes are associated with improved overall survival in follicular lymphoma. J Clin Oncol 2009;27:1470-1476.
[PubMed]
44.
Takahashi H, Tomita N, Sakata S, Tsuyama N, Hashimoto C, Ohshima R, Matsuura S, Ogawa K, Yamamoto W, Kameda Y, Enaka M, Inayama Y, Kasahara M, Takekawa Y, Onoda N, Motomura S, Ishigatsubo Y, Takeuchi K: Prognostic significance of programmed cell death-1-positive cells in follicular lymphoma patients may alter in the rituximab era. Eur J Haematol 2013;90:286-290.
[PubMed]
45.
Yang ZZ, Grote DM, Ziesmer SC, Ansell SM: PD-1 expression defines two distinct T-cell subpopulations that differentially impact patient outcomes in follicular lymphoma. Blood 2013;122:366.
46.
Yamamoto R, Nishikori M, Kitawaki T, Sakai T, Hishizawa M, Tashima M, Kondo T, Ohmori K, Kurata M, Hayashi T, Uchiyama T: PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood 2008;111:3220-3224.
[PubMed]
47.
Green MR, Monti S, Rodig SJ, Juszczynski P, Currie T, O'Donnell E, Chapuy B, Takeyama K, Neuberg D, Golub TR, Kutok JL, Shipp MA: Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 2010;116:3268-3277.
[PubMed]
48.
Chen BJ, Chapuy B, Ouyang J, Sun HH, Roemer MGM, Xu ML, Yu H, Fletcher CDM, Freeman GJ, Shipp MA, Rodig SJ: PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res 2013;19:3462-3473.
[PubMed]
49.
Grote DM, Ziesmer SC, Hodge LS, Price-Troska TL, Novak AJ, Yang ZZ: Interactions between PD-1 and PD-L1 and PD-L2 promote malignant B-cell growth in Waldenström macroglobulinemia. Blood 2013;122:4334.
50.
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N: Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA 2002;99:12293-12297.
[PubMed]
51.
Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D, Saudemont A, Quesnel B: Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with INF-γ and TLR ligands via a MYD88-, TRAF6-, and MEK-dependent pathway. Blood 2007;110:296-304.
[PubMed]
52.
Hallett WH, Jing W, Drobyski WR, Johnson BD: Immunosuppressive effects of multiple myeloma are overcome by PD-L1 blockade. Biol Blood Marrow Transplant 2011;17:1133-1145.
[PubMed]
53.
Kearl TJ, Jing W, Gershan JA, Johnson BD: Programmed death receptor-1/programmed death receptor ligand-1 blockade after transient lymphodepletion to treat myeloma. J Immunol 2013;190:5620-5628.
[PubMed]
54.
Benson DM Jr, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B, Baiocchi RA, Zhang J, Yu J, Smith MK, Greenfield CN, Porcu P, Devine SM, Rotem-Yehudar R, Lozanski G, Byrd JC, Caligiuri MA: The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood 2010;116:2286-2294.
[PubMed]
55.
Luptakova K, Rosenblatt J, Glotzbecker B, Mills H, Stroopinsky D, Kufe T, Vasir B, Arnason J, Tzachanis D, Zwicker JI, Joyce RM, Levine JD, Anderson KC, Kufe D, Avigan D: Lenalidomide enhances anti-myeloma cellular immunity. Cancer Immunol Immunother 2013;62:39-49.
[PubMed]
56.
Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, Koren-Michowitz M, Shimoni A, Nagler A: Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res 2008;14:3044-3051.
[PubMed]
57.
Westin JR, Chu F, Foglietta M, Rotem-Yehudar R, Neelapu SS: Phase II safety and efficacy study of CT-011, a humanized anti-PD-1 monoclonal antibody, in combination with rituximab in patients with relapsed follicular lymphoma. ASCO Meeting Abstracts, 2010, vol 28, abstract TPS305.
58.
Westin JR, Chu F, Zhang M, Fayad LE, Kwak LW, Fowler N, Romaguera J, Hagemeister F, Fanale M, Samaniego F, Feng L, Baladandayuthapani V, Wang Z, Ma W, Gao Y, Wallace M, Vence LM, Radvanyi L, Muzzafar T, Rotem-Yehudar R, Davis RE, Neelapu SS: Safety and activity of PD-1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol 2014;15:69-77.
[PubMed]
59.
Bachy E, Coiffier B: Anti-PD-1 antibody: a new approach to treatment of lymphomas. Lancet Oncol 2014;15:7-8.
[PubMed]
60.
Armand P, Nagler A, Weller EA, Devine SM, Avigan DE, Chen YB, Kaminski MS, Holland HK, Winter JN, Mason JR, Fay JW, Rizzieri DA, Hosing CM, Ball ED, Uberti JP, Lazarus HM, Mapara MY, Gregory SA, Timmerman JM, Andorsky D, Or R, Waller EK, Rotem-Yehudar R, Gordon LI: Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J Clin Oncol 2013;31:4199-4206.
[PubMed]
61.
Jacobsen ED: Restoring antitumor immunity via PD-1 blockade after autologous stem-cell transplantation for diffuse large B-cell lymphoma. J Clin Oncol 2013;31:4268-4270.
[PubMed]
You do not currently have access to this content.