Top

Published in:

01-02-2018 | Review Article

B7-H3 in tumors: friend or foe for tumor immunity?

Authors: Gen Li, Yanchun Quan, Fengyuan Che, Lijuan Wang

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2018

Abstract

B7-H3 is a type I transmembrane co-stimulatory molecule of the B7 family. B7-H3 mRNA is widely distributed in most tissues; however, B7-H3 protein is not constitutively expressed. Few molecules have been shown to mediate the regulation of B7-H3 expression, and their regulatory mechanisms remain unexplored. Recently, TREM-like transcript 2 (TLT-2) has been identified as a potential receptor of B7-H3. However, TLT-2 may not be the only receptor of B7-H3, as B7-H3 has many contradictory roles. As a co-stimulatory molecule, B7-H3 increases the proliferation of both CD4+ and CD8+ T-cells and enhances cytotoxic T-cell activity. However, greatly increased T-cell proliferation and IL-2 levels have been observed in the absence of B7-H3. Thus far, it has been shown that various tumors test positive for B7-H3 expression and that B7-H3 levels correlate with tumor growth, invasion, metastasis, malignant stage, and recurrence rate. Furthermore, transfection of cells with a B7-H3 plasmid and treatment with monoclonal antibodies to block B7-H3 are the main immunotherapeutic strategies for cancer treatment. Several groups have generated anti-B7-H3 antibodies and observed tumor growth suppression in vitro and in vivo. Therefore, it is likely that B7-H3 plays an important role in cancer diagnosis and treatment, aside from its role as a co-stimulatory molecule.

Mockler MB, Conroy MJ, Lysaght J (2014) Targeting T cell immunometabolism for cancer immunotherapy; understanding the impact of the tumor microenvironment. Front Oncol 4:107. https://doi.org/10.3389/fonc.2014.00107CrossRefPubMedPubMedCentral

Fauci JM, Michael Straughn J Jr et al (2012) A review of B7-H3 and B7-H4 immune molecules and their role in ovarian cancer. Gynecol Oncol 127(2):420–425. https://doi.org/10.1016/j.ygyno.2012.08.017CrossRefPubMed

Pollizzi KN, Powell JD (2014) Integrating canonical and metabolic signalling programmes in the regulation of T cell responses. Nat Rev Immunol 14(7):435–446. https://doi.org/10.1038/nri3701CrossRefPubMedPubMedCentral

Loos M, Hedderich DM et al (2010) B7-H3 and its role in antitumor immunity. Clin Dev Immunol 2010:683875. https://doi.org/10.1155/2010/683875CrossRefPubMedPubMedCentral

Freedman AS, Freeman G, Horowitz JC, Daley J, Nadler LM (1987) B7, a B-cell-restricted antigen that identifies preactivated B cells. J Immunol 139(10):3260–3267PubMed

Greaves P, Gribben JG (2013) The role of B7 family molecules in hematologic malignancy. Blood 121(5):734–744. https://doi.org/10.1182/blood-2012-10-385591CrossRefPubMedPubMedCentral

Leung J, Suh WK (2014) The CD28-B7 family in anti-tumor immunity: emerging concepts in cancer immunotherapy. Immune Netw 14(6):265–276. https://doi.org/10.4110/in.2014.14.6.265CrossRefPubMedPubMedCentral

Zhao R, Chinai JM et al (2013) HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function. Proc Natl Acad Sci USA 110(24):9879–9884. https://doi.org/10.1073/pnas.1303524110CrossRefPubMedPubMedCentral

Zhou Y, Xu Y et al (2015) B7-H6 expression correlates with cancer progression and patient’s survival in human ovarian cancer. Int J Clin Exp Pathol 8(8):9428–9433PubMedPubMedCentral

10.

Chapoval AI, Ni J et al (2001) B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Nat Immunol 2(3):269–274. https://doi.org/10.1038/85339CrossRefPubMed

11.

Zang X, Thompson RH et al (2007) B7-H3 and B7x are highly expressed in human prostate cancer and associated with disease spread and poor outcome. Proc Natl Acad Sci USA 104(49):19458–19463. https://doi.org/10.1073/pnas.0709802104CrossRefPubMedPubMedCentral

12.

Hofmeyer KA, Ray A, Zang X (2008) The contrasting role of B7-H3. Proc Natl Acad Sci USA 105(30):10277–10278. https://doi.org/10.1073/pnas.0805458105CrossRefPubMedPubMedCentral

13.

Wang L, Kang FB, Shan BE (2014) B7-H3-mediated tumor immunology: friend or foe?. Int J Cancer 134(12): 2764–2771. https://doi.org/10.1002/ijc.28474CrossRefPubMed

14.

Steinberger P, Majdic O et al (2004) Molecular characterization of human 4Ig-B7-H3, a member of the B7 family with four Ig-like domains. J Immunol 172(4):2352–2359CrossRefPubMed

15.

Wang L, Fraser CC et al (2005) B7-H3 promotes acute and chronic allograft rejection. Eur J Immunol 35(2): 428–438. https://doi.org/10.1002/eji.200425518CrossRefPubMed

16.

Sun M, Richards S et al (2002) Characterization of mouse and human B7-H3 genes. J Immunol 168(12):6294–6297CrossRefPubMed

17.

Shi J, Zhang DL, Cui ZC, Wang HM. (2016) Preparation and application of a novel monoclonal antibody specific for human B7-H3. Mol Med Rep. 14(1):943–948. https://doi.org/10.3892/mmr.2016.5288CrossRefPubMed

18.

Zhou YH, Chen YJ et al (2007) 4IgB7-H3 is the major isoform expressed on immunocytes as well as malignant cells. Tissue Antigens 70(2):96–104. https://doi.org/10.1111/j.1399-0039.2007.00853.xCrossRefPubMed

19.

Zhang G, Hou J et al (2008) Soluble CD276 (B7-H3) is released from monocytes, dendritic cells and activated T cells and is detectable in normal human serum. Immunology 123(4):538–546. https://doi.org/10.1111/j.1365-2567.2007.02723.xCrossRefPubMedPubMedCentral

20.

Greenwald RJ, Freeman GJ, Sharpe AH (2005) The B7 family revisited. Annu Rev Immunol 23: 515–548. https://doi.org/10.1146/annurev.immunol.23.021704.115611CrossRefPubMed

21.

Calabrò L, Sigalotti L et al (2011) Expression and regulation of B7-H3 immunoregulatory receptor, in human mesothelial and mesothelioma cells: immunotherapeutic implications. J Cell Physiol 226(10):2595–2600. https://doi.org/10.1002/jcp.22600

22.

Suh WK, Gajewska BU et al (2003) The B7 family member B7-H3 preferentially down-regulates T helper type 1-mediated immune responses. Nat Immunol 4(9):899–906. https://doi.org/10.1038/ni967CrossRefPubMed

23.

Sun J, Guo Y et al (2014) B7-H3 expression in breast cancer and upregulation of VEGF through gene silence. Onco Targets Ther 7: 1979–1986. https://doi.org/10.2147/OTT.S63424CrossRefPubMedPubMedCentral

24.

Yi KH, Chen L (2009) Fine tuning the immune response through B7-H3 and B7-H4. Immunol Rev 229(1):145–151. https://doi.org/10.1111/j.1600-065X.2009.00768.xCrossRefPubMedPubMedCentral

25.

Bachawal SV, Jensen KC et al (2015) Breast cancer detection by B7-H3-targeted ultrasound molecular imaging. Cancer Res 75(12):2501–2509. https://doi.org/10.1158/0008-5472.CAN-14-3361CrossRefPubMedPubMedCentral

26.

Liu C, Liu J et al (2013) B7-H3 expression in ductal and lobular breast cancer and its association with IL-10. Mol Med Rep 7(1):134–138CrossRefPubMed

27.

Zang X, Sullivan PS et al (2010) Tumor associated endothelial expression of B7-H3 predicts survival in ovarian carcinomas. Mod Pathol 23(8):1104–1112. https://doi.org/10.1038/modpathol.2010.95CrossRefPubMedPubMedCentral

28.

Mao Y, Sun J et al (2013) Clinical significance of costimulatory molecule B7-H3 expression on CD3(+) T cells in colorectal carcinoma. Chin Med J (Engl) 126(16):3035–3038

29.

Sun J, Chen L et al (2010) Clinical significance and regulation of the costimulatory molecule B7-H3 in human colorectal carcinoma. Cancer Immunol Immunother 59(8):1163–1171. https://doi.org/10.1007/s00262-010-0841-1CrossRefPubMed

30.

Roth TJ, Sheinin Y et al (2007) B7-H3 ligand expression by prostate cancer: a novel marker of prognosis and potential target for therapy. Cancer Res 67(16):7893–7900. https://doi.org/10.1158/0008-5472.CAN-07-1068

31.

Benzon B, Zhao SG et al (2017) Correlation of B7-H3 with androgen receptor, immune pathways and poor outcome in prostate cancer: an expression-based analysis. Prostate Cancer Prostatic Dis 20(1):28–35. https://doi.org/10.1038/pcan.2016.49CrossRefPubMed

32.

Loos M, Hedderich DM et al (2009) Expression of the costimulatory molecule B7-H3 is associated with prolonged survival in human pancreatic cancer. BMC Cancer 9:463. https://doi.org/10.1186/1471-2407-9-463CrossRefPubMedPubMedCentral

33.

Zhao X, Li D et al (2013) B7-H3 overexpression in pancreatic cancer promotes tumor progression. Int J Mol Med 31(2):283–291. https://doi.org/10.3892/ijmm.2012.1212CrossRefPubMed

34.

Yamato I, Sho M et al (2009) Clinical importance of B7-H3 expression in human pancreatic cancer. Br J Cancer 101(10):1709–1716. https://doi.org/10.1038/sj.bjc.6605375CrossRefPubMedPubMedCentral

35.

Zhang SS, Tang J et al (2015) Expression levels of B7-H3 and TLT-2 in human oral squamous cell carcinoma. Oncol Lett 10(2):1063–1068. https://doi.org/10.3892/ol.2015.3274CrossRefPubMedPubMedCentral

36.

Katayama A, Takahara M et al (2011) Expression of B7-H3 in hypopharyngeal squamous cell carcinoma as a predictive indicator for tumor metastasis and prognosis. Int J Oncol 38(5):1219–1226. https://doi.org/10.3892/ijo.2011.949CrossRefPubMed

37.

Boland JM, Kwon ED et al (2013) Tumor B7-H1 and B7-H3 expression in squamous cell carcinoma of the lung. Clin Lung Cancer 14(2):157–163. https://doi.org/10.1016/j.cllc.2012.05.006CrossRefPubMed

38.

Sun Y, Wang Y et al (2006) B7-H3 and B7-H4 expression in non-small-cell lung cancer. Lung Cancer 53(2):143–151. https://doi.org/10.1016/j.lungcan.2006.05.012CrossRefPubMed

39.

Xu YH, Zhang GB, Wang JM, Hu HC et al (2010) B7-H3 and CD133 expression in non-small cell lung cancer and correlation with clinicopathologic factors and prognosis. Saudi Med J 31(9):980–986PubMed

40.

Wu CP, Jiang JT et al (2006) Relationship between co-stimulatory molecule B7-H3 expression and gastric carcinoma histology and prognosis. World J Gastroenterol 12(3):457–459CrossRefPubMedPubMedCentral

41.

Arigami T, Uenosono Y et al (2011) B7-H3 expression in gastric cancer: a novel molecular blood marker for detecting circulating tumor cells. Cancer Sci 102(5):1019–1024. https://doi.org/10.1111/j.1349-7006.2011.01877.xCrossRefPubMed

42.

Li Y, Yang X et al (2017) B7-H3 promotes gastric cancer cell migration and invasion. Oncotarget. http://doi.org/10.18632/oncotarget.17847

43.

Shevach EM, McHugh RS et al (2001) Control of T-cell activation by CD4+ CD25+ suppressor T cells. Immunol Rev 182:58–67. https://doi.org/10.1034/j.1600-065X.2001.1820104.xCrossRefPubMed

44.

Mahnke K, Ring S et al (2007) Induction of immunosuppressive functions of dendritic cells in vivo by CD4+ CD25+ regulatory T cells: role of B7-H3 expression and antigen presentation. Eur J Immunol 37(8):2117–2126. https://doi.org/10.1002/eji.200636841CrossRefPubMed

45.

Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297. https://doi.org/10.1016/S0092-8674(04)00045-5CrossRefPubMed

46.

Gao B, Chen H et al (2015) MiR-29a inhibited costimulatory molecule B7-H3 expression and the invasion of glioma growth. Chin J Cancer Biother 22(1):28–33. https://doi.org/10.3872/j.issn.1007-385X.2015.1.005

47.

Xu H, Cheung IY et al (2009) MicroRNA miR-29 modulates expression of immunoinhibitory molecule B7-H3: potential implications for immune based therapy of human solid tumors. Cancer Res 69(15):6275–6281. https://doi.org/10.1158/0008-5472.CAN-08-4517CrossRefPubMedPubMedCentral

48.

Wang J, Chong KK et al (2013) B7-H3 associated with tumor progression and epigenetic regulatory activity in cutaneous melanoma. J Invest Dermatol 133(8):2050–2058. https://doi.org/10.1038/jid.2013.114CrossRefPubMedPubMedCentral

49.

Colonna M, Nakajima H, Cella M (2000) A family of inhibitory and activating Ig-like receptors that modulate function of lymphoid and myeloid cells. Semin Immunol 12(2):121–127. https://doi.org/10.1006/smim.2000.0214CrossRefPubMed

50.

Zhang P, Yu S et al (2015) ILT4 drives B7-H3 expression via PI3K/AKT/mTOR signalling and ILT4/B7-H3 co-expression correlates with poor prognosis in non-small cell lung cancer. FEBS Lett 589(17):2248–2256. https://doi.org/10.1016/j.febslet.2015.06.037CrossRefPubMed

51.

Linsley PS, Greene JL et al (1994) Human B7–1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1(9):793–801. https://doi.org/10.1016/S1074-7613(94)80021-9CrossRefPubMed

52.

Brandt CS, Baratin M et al (2009) The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans. J Exp Med 206(7):1495–1503. https://doi.org/10.1084/jem.20090681CrossRefPubMedPubMedCentral

53.

Hashiguchi M, Kobori H et al (2008) Triggering receptor expressed on myeloid cell-like transcript 2 (TLT-2) is a counter-receptor for B7-H3 and enhances T cell responses. Proc Natl Acad Sci USA 105(30):10495–10500. https://doi.org/10.1073/pnas.0802423105CrossRefPubMedPubMedCentral

54.

Hashiguchi M, Inamochi Y et al (2012) Human B7-H3 binds to Triggering receptor expressed on myeloid cells-like transcript 2 (TLT-2) and enhances T cell responses. Open J Immunol 2(1):9–16. https://doi.org/10.4236/oji.2012.21002CrossRef

55.

King RG, Herrin BR, Justement LB (2006) Trem-like transcript 2 is expressed on cells of the myeloid/granuloid and B lymphoid lineage and is up-regulated in response to inflammation. J Immunol 176(10):6012–6021CrossRefPubMed

56.

Leitner J, Klauser C et al (2009) B7-H3 is a potent inhibitor of human T-cell activation: No evidence for B7-H3 and TREML2 interaction. Eur J Immunol 39(7):1754–1764. https://doi.org/10.1002/eji.200839028CrossRefPubMedPubMedCentral

57.

Vigdorovich V, Ramagopal UA et al (2013) Structure and T cell inhibition properties of B7 family member, B7-H3. Structure 21(5):707–717. https://doi.org/10.1016/j.str.2013.03.003CrossRefPubMedPubMedCentral

58.

Harris NL, Ronchese F (1999) The role of B7 costimulation in T-cell immunity. Immunol Cell Biol 77(4):304–311. https://doi.org/10.1046/j.1440-1711.1999.00835.x

59.

Zhang P, Martin M et al (2004) Role of B7 costimulatory molecules in immune responses and T-helper cell differentiation in response to recombinant HagB from Porphyromonas gingivalis. Infect Immun 72(2):637–644CrossRefPubMedPubMedCentral

60.

Lupu CM, Eisenbach C et al (2007) Adenoviral B7-H3 therapy induces tumor specific immune responses and reduces secondary metastasis in a murine model of colon cancer. Oncol Rep 18(3):745–748PubMed

61.

Lupu CM, Eisenbach C et al (2006) An orthotopic colon cancer model for studying the B7-H3 antitumor effect in vivo. J Gastrointest Surg 10(5):635–645. https://doi.org/10.1016/j.gassur.2006.02.001CrossRefPubMed

62.

Luo L, Chapoval AI et al (2004) B7-H3 enhances tumor immunity in vivo by costimulating rapid clonal expansion of antigen-specific CD8+ cytolytic T cells. J Immunol 173(9):5445–5450. https://doi.org/10.4049/jimmunol.173.9.5445CrossRefPubMed

63.

Luo L, Zhu G et al (2015) B7-H3 promotes pathogenesis of autoimmune disease and inflammation by regulating the activity of different T cell subsets. PLoS One 10(6):e0130126. https://doi.org/10.1371/journal.pone.0130126CrossRefPubMedPubMedCentral

64.

Prasad DV, Nguyen T et al (2004) Murine B7-H3 is a negative regulator of T cells. J Immunol 173(4):2500–2506. https://doi.org/10.4049/jimmunol.173.4.2500CrossRefPubMed

65.

Fukushima A, Sumi T et al (2007) B7-H3 regulates the development of experimental allergic conjunctivitis in mice. Immunol Lett 113(1):52–57. https://doi.org/10.1016/j.imlet.2007.07.011CrossRefPubMed

66.

Kreymborg K, Haak S et al (2015) Ablation of B7-H3 but Not B7-H4 Results in highly increased tumor burden in a murine model of spontaneous prostate cancer. Cancer Immunol Res 3(8):849–854. https://doi.org/10.1158/2326-6066.CIR-15-0100CrossRefPubMed

67.

Castriconi R, Dondero A et al (2004) Identification of 4Ig-B7-H3 as a neuroblastoma-associated molecule that exerts a protective role from an NK cell-mediated lysis. Proc Natl Acad Sci USA 101(34):12640–12645. https://doi.org/10.1073/pnas.0405025101CrossRefPubMedPubMedCentral

68.

Jin Y, Zhang P et al (2015) B7-H3 in combination with regulatory T cell is associated with tumor progression in primary human non-small cell lung cancer. Int J Clin Exp Pathol 8(11):13987–13995PubMedPubMedCentral

69.

Sun TW, Gao Q et al (2012) B7-H3 is expressed in human hepatocellular carcinoma and is associated with tumor aggressiveness and postoperative recurrence. Cancer Immunol Immunother 61(11):2171–2182. https://doi.org/10.1007/s00262-012-1278-5CrossRefPubMed

70.

Wang L, Zhang Q et al (2013) B7-H3 is overexpressed in patients suffering osteosarcoma and associated with tumor aggressiveness and metastasis. PLoS One 8(8): e70689. https://doi.org/10.1371/journal.pone.0070689CrossRefPubMedPubMedCentral

71.

Maeda N, Yoshimura K et al (2014) Expression of B7-H3, a potential factor of tumor immune evasion in combination with the number of regulatory T cells, affects against recurrence-free survival in breast cancer patients. Ann Surg Oncol 21(Suppl 4):S546-S554. https://doi.org/10.1245/s10434-014-3564-2

72.

Li Y, Guo G et al (2017) B7-H3 promotes the migration and invasion of human bladder cancer cells via the PI3K/Akt/STAT3 signaling pathway. J Cancer 8(5):816–824. https://doi.org/10.7150/jca.17759CrossRefPubMedPubMedCentral

73.

Yuan H, Wei X et al (2011) B7-H3 over expression in prostate cancer promotes tumor cell progression. J Urol 186(3):1093–1099. https://doi.org/10.1016/j.juro.2011.04.103CrossRefPubMed

74.

Zhang T, Jiang B et al (2015) Overexpression of B7-H3 augments anti-apoptosis of colorectal cancer cells by Jak2-STAT3. World J Gastroenterol 21(6):1804–1813. https://doi.org/10.3748/wjg.v21.i6.1804CrossRefPubMedPubMedCentral

75.

Zhang W, Wang J et al (2015) B7-H3 silencing by RNAi inhibits tumor progression and enhances chemosensitivity in U937 cells. Onco Targets Ther 8:1721–1733. https://doi.org/10.2147/OTT.S85272CrossRefPubMedPubMedCentral

76.

Lemke D, Pfenning PN et al (2012) Costimulatory protein 4IgB7H3 drives the malignant phenotype of glioblastoma by mediating immune escape and invasiveness. Clin Cancer Res 18(1):105–117. https://doi.org/10.1158/1078-0432.CCR-11-0880CrossRefPubMed

77.

Sun X, Vale M et al (2003) Mouse B7-H3 induces antitumor immunity. Gene Ther 10(20): 1728–1734. https://doi.org/10.1038/sj.gt.3302070CrossRefPubMed

78.

Chen L, Zhang G et al (2016) Upregulation of soluble B7-H3 in NSCLC-derived malignant pleural effusion: a potential diagnostic biomarker correlated with NSCLC staging. Clin Chim Acta 457:81–85. https://doi.org/10.1016/j.cca.2016.04.009CrossRefPubMed

79.

Chao X, Liu D et al (2016) Soluble B7-H3 promotes the invasion and metastasis of pancreatic carcinoma cells through the TLR4/NF-κB pathway. Sci Rep 6:27528. https://doi.org/10.1038/srep27528CrossRef

80.

Yang HY, Chu M et al (2008) Transgenic B7-H3 therapy induces tumor-specific immune response in human oral squamous cell cancer: an in vitro study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 106(5):721–728. https://doi.org/10.1016/j.tripleo.2008.08.012CrossRefPubMed

81.

Ma L, Luo L et al (2007) Complete eradication of hepatocellular carcinomas by combined vasostatin gene therapy and B7H3-mediated immunotherapy. J Hepatol 46(1):98–106. https://doi.org/10.1016/j.jhep.2006.07.031CrossRefPubMed

82.

Loo D, Alderson RF et al (2012) Development of an Fc-enhanced anti-B7-H3 monoclonal antibody with potent antitumor activity. Clin Cancer Res 18(14):3834–3845. https://doi.org/10.1158/1078-0432.CCR-12-0715CrossRefPubMed

83.

Fauci JM, Sabbatino F et al (2014) Monoclonal antibody-based immunotherapy of ovarian cancer: targeting ovarian cancer cells with the B7-H3-specific mAb 376.96. Gynecol Oncol 132(1):203–210. https://doi.org/10.1016/j.ygyno.2013.10.038CrossRefPubMed

84.

Ma J, Ma P et al (2016) B7-H3 as a promising target for cytotoxicity T cell in human cancer therapy. Oncotarget 7(20): 29480–29491. https://doi.org/10.18632/oncotarget.8784PubMedPubMedCentral

Title: B7-H3 in tumors: friend or foe for tumor immunity?
Authors: Gen Li
Yanchun Quan
Fengyuan Che
Lijuan Wang
Publication date: 01-02-2018
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2018
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-017-3508-1

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2018

A phase II trial of Ifosfamide combination with recommended supportive therapy for recurrent SCLC in second-line and heavily treated setting

Prediction of neutrophil reduction using plasma paclitaxel concentration after administration in patients with uterine, ovarian, or cervical cancers in an outpatient clinic

The impact of skeletal muscle on the pharmacokinetics and toxicity of 5-fluorouracil in colorectal cancer

Pharmacokinetically-targeted dosed everolimus maintenance therapy in lymphoma patients

Correction to: Ibrutinib does not prolong the corrected QT interval in healthy subjects: results from a thorough QT study

Acknowledgement of reviewers 2016

Keynote webinar | Spotlight on antibody–drug conjugates in cancer