OX40 (CD134) and OX40 ligand, important immune checkpoints in cancer

Juan Deng, Sha Zhao, Xiaoshen Zhang, Keyi Jia, Hao Wang, Caicun Zhou, Yayi He, Juan Deng, Sha Zhao, Xiaoshen Zhang, Keyi Jia, Hao Wang, Caicun Zhou, Yayi He

Abstract

Immunotherapy has shown promising results in cancer treatment. Research shows that most patients might be resistant to these therapies. So, new immune therapies are needed. OX40 (CD134) and OX40 ligand (OX40L), costimulatory molecules, express on different types of immune cells. The interaction between OX40 and OX40L (OX40/OX40L) induces the expansion and proliferation of T cells and decreases the immunosuppression of regulatory T (Treg) cells to enhance the immune response to the specific antigen. For the important role OX40 takes in the process of immunity, many clinical trials are focusing on OX40 to find out whether it may have active effects in clinical cancer treatment. The results of clinical trials are still not enough. So, we reviewed the OX40 and its ligand (OX40L) function in cancer, clinical trials with OX40/OX40L and the correlation between OX40/OX40L and other immune checkpoints to add more ideas to tumor feasible treatment.

Keywords: OX40/OX40L; cancer; immune checkpoints; immunotherapy.

Conflict of interest statement

The authors report no conflicts of interest in this work.

© 2019 Deng et al.

Figures

Figure 1
Figure 1
OX40–OX40L interaction model. Abbreviations: Th2, T helper 2; NK, natural killer; TCR, T cell receptor; MHC, major histocompatibility complex; APC, antigen presenting cell.

References

    1. Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science. 2013;342:1432–1433. doi:10.1126/science.342.6165.1432
    1. He Y, Rivard CJ, Rozeboom L, et al. Lymphocyte-activation gene-3, an important immune checkpoint in cancer. Cancer Sci. 2016;107:1193–1197. doi:10.1111/cas.12986
    1. He Y, Rozeboom L, Rivard CJ, et al. PD-1, PD-L1 protein expression in non-small cell lung cancer and their relationship with tumor-infiltrating lymphocytes. Med Sci Monit. 2017;23:1208–1216. doi:10.12659/msm.899909
    1. He Y, Rozeboom L, Rivard CJ, et al. MHC class II expression in lung cancer. Lung Cancer. 2017;112:75–80. doi:10.1016/j.lungcan.2017.07.030
    1. He Y, Yu H, Rozeboom L, et al. LAG-3 protein expression in non-small cell lung cancer and its relationship with PD-1/PD-L1 and tumor-infiltrating lymphocytes. J Thorac Oncol. 2017;12:814–823. doi:10.1016/j.jtho.2017.01.019
    1. Bilusic M, Madan RA, Gulley JL. Immunotherapy of prostate cancer: Facts and hopes. Clin Cancer Res. 2017;23:6764–6770. doi:10.1158/1078-0432.ccr-17-0019
    1. Dushyanthen S, Teo ZL, Caramia F, et al. Agonist immunotherapy restores T cell function following MEK inhibition improving efficacy in breast cancer. Nat Commun. 2017;8:606. doi:10.1038/s41467-017-00728-9
    1. Carboni S, Aboul-Enein F, Waltzinger C, Killeen N, Lassmann H, Peña-Rossi C. CD134 plays a crucial role in the pathogenesis of EAE and is upregulated in the CNS of patients with multiple sclerosis. J Neuroimmunol. 2003;145:1–11.
    1. Ali SA, Ahmad M, Lynam J, et al. Anti-tumour therapeutic efficacy of OX40L in murine tumour model. Vaccine. 2004;22:3585–3594. doi:10.1016/j.vaccine.2004.03.041
    1. Kim BS, Kim JY, Kim EJ, et al. Role of thalidomide on the expression of OX40, 4-1BB, and GITR in T cell subsets. Transplant Proc. 2016;48:1270–1274. doi:10.1016/j.transproceed.2015.12.088
    1. Soroosh P, Ine S, Sugamura K, Ishii N. OX40-OX40 ligand interaction through T cell-T cell contact contributes to CD4 T cell longevity. J Immunol. 2006;176:5975–5987. doi:10.4049/jimmunol.176.10.5975
    1. Rogers PR, Song J, Gramaglia I, Killeen N, Croft M. OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells. Immunity. 2001;15:445–455.
    1. Jones RG, Parsons M, Bonnard M, et al. Protein kinase B regulates T lymphocyte survival, nuclear factor kappaB activation, and Bcl-X(L) levels in vivo. J Exp Med. 2000;191:1721–1734. doi:10.1084/jem.191.10.1721
    1. Kinnear G, Wood KJ, Marshall D, Jones ND. Anti-OX40 prevents effector T-cell accumulation and CD8+ T-cell mediated skin allograft rejection. Transplantation. 2010;90:1265–1271. doi:10.1097/TP.0b013e3181fe5396
    1. Flynn S, Toellner KM, Raykundalia C, Goodall M, Lane P. CD4 T cell cytokine differentiation: the B cell activation molecule, OX40 ligand, instructs CD4 T cells to express interleukin 4 and upregulates expression of the chemokine receptor, Blr-1. J Exp Med. 1998;188:297–304. doi:10.1084/jem.188.2.297
    1. Vu MD, Clarkson MR, Yagita H, Turka LA, Sayegh MH, Li XC. Critical, but conditional, role of OX40 in memory T cell-mediated rejection. J Immunol. 2006;176:1394–1401. doi:10.4049/jimmunol.176.3.1394
    1. Linton P-J, Bautista B, Biederman E, et al. Costimulation via OX40L expressed by B cells is sufficient to determine the extent of primary CD4 cell expansion and Th2 cytokine secretion in vivo. J Exp Med. 2003;197:875–883. doi:10.1084/jem.20021290
    1. Nuebling T, Schumacher CE, Hofmann M, et al. The immune checkpoint modulator OX40 and its ligand OX40L in NK-cell immunosurveillance and acute myeloid leukemia. Cancer Immunol Res. 2018;6:209–221. doi:10.1158/2326-6066.CIR-17-0212
    1. Pollmann J, Götz -J-J, Rupp D, et al. Hepatitis C virus-induced natural killer cell proliferation involves monocyte-derived cells and the OX40/OX40L axis. J Hepatol. 2018;68:421–430. doi:10.1016/j.jhep.2017.10.021
    1. Turaj AH, Cox KL, Penfold CA, et al. Augmentation of CD134 (OX40)-dependent NK anti-tumour activity is dependent on antibody cross-linking. Sci Rep. 2018;8:2278. doi:10.1038/s41598-018-20656-y
    1. Li F, Wang Y, Lin L, et al. Mast cell-derived exosomes promote Th2 cell differentiation via OX40L-OX40 ligation. J Immunol Res. 2016;2016:1–10. doi:10.1155/2016/3623898
    1. Takeda I, Ine S, Killeen N, et al. Distinct roles for the OX40-OX40 ligand interaction in regulatory and nonregulatory T cells. J Immunol. 2004;172:3580–3589. doi:10.4049/jimmunol.172.6.3580
    1. Piconese S, Pittoni P, Burocchi A, et al. A non-redundant role for OX40 in the competitive fitness of Treg in response to IL-2. Eur J Immunol. 2010;40:2902–2913. doi:10.1002/eji.201040505
    1. Wang Q, Shi B-M, Xie F, et al. Enhancement of CD4(+) T cell response and survival via coexpressed OX40/OX40L in Graves’ disease. Mol Cell Endocrinol. 2016;430:115–124. doi:10.1016/j.mce.2016.04.008
    1. Jiang J, Liu C, Liu M, et al. OX40 signaling is involved in the autoactivation of CD4(+)CD28(-) T cells and contributes to the pathogenesis of autoimmune arthritis. Arthritis Res Ther. 2017;19:67. doi:10.1186/s13075-017-1261-9
    1. Wu X, Rosenbaum JT, Adamus G, et al. Activation of OX40 prolongs and exacerbates autoimmune experimental uveitis. Invest Ophthalmol Vis Sci. 2011;52:8520–8526. doi:10.1167/iovs.11-7664
    1. Yoshioka T, Nakajima A, Akiba H, et al. Contribution of OX40/OX40 ligand interaction to the pathogenesis of rheumatoid arthritis. Eur J Immunol. 2000;30:2815–2823. doi:10.1002/1521-4141(200010)30:10<2815::AID-IMMU2815>;2-#
    1. Boettler T, Moeckel F, Cheng Y, et al. OX40 facilitates control of a persistent virus infection. PLoS Pathog. 2012;8:e1002913. doi:10.1371/journal.ppat.1002913
    1. Tahiliani V, Hutchinson TE. OX40 cooperates with ICOS to amplify follicular th cell development and germinal center reactions during infection. J Immunol. 2017;198:218–228. doi:10.4049/jimmunol.1601356
    1. Boettler T, Choi YS, Salek-Ardakani S, et al. Exogenous OX40 stimulation during lymphocytic choriomeningitis virus infection impairs follicular Th cell differentiation and diverts CD4 T cells into the effector lineage by upregulating Blimp-1. J Immunol. 2013;191:5026–5035. doi:10.4049/jimmunol.1300013
    1. Curry AJ, Chikwe J, Smith XG, et al. OX40 (CD134) blockade inhibits the co-stimulatory cascade and promotes heart allograft survival. Transplantation. 2004;78:807–814. doi:10.1097/01.tp.0000131670.99000.54
    1. Tripathi T, Yin W, Xue Y, et al. Central roles of OX40L-OX40 interaction in the induction and progression of human T cell-driven acute graft-versus-host disease. ImmunoHorizons. 2019;3:110–120. doi:10.4049/immunohorizons.1900001
    1. Li T, Ma R, Zhu J, Wang F, Huang L, Leng X. Blockade of the OX40/OX40L pathway and induction of PD-L1 synergistically protects mouse islet allografts from rejection. Chin Med J. 2014;127:2686–2692.
    1. Kinnear G, Wood KJ, Fallah-Arani F, Jones ND. A diametric role for OX40 in the response of effector/memory CD4+ T cells and regulatory T cells to alloantigen. J Immunol. 2013;191:1465–1475. doi:10.4049/jimmunol.1300553
    1. Elhai M, Avouac J, Hoffmann-Vold AM, et al. OX40L blockade protects against inflammation-driven fibrosis. Proc Natl Acad Sci U S A. 2016;113:E3901–E3910. doi:10.1073/pnas.1523512113
    1. Boleto G, Allanore Y, Avouac J. Targeting costimulatory pathways in systemic sclerosis. Front Immunol. 2018;9:2998. doi:10.3389/fimmu.2018.02998
    1. Papadopoulos C, Terzis G, Papadimas GK, Manta P. OX40-OX40L expression in idiopathic inflammatory myopathies. Anal Quant Cytol Histol. 2013;35:17–26.
    1. Totsuka T, Kanai T, Uraushihara K, et al. Therapeutic effect of anti-OX40L and anti-TNF-alpha MAbs in a murine model of chronic colitis. Am J Physiol Gastrointest Liver Physiol. 2003;284:G595–G603. doi:10.1152/ajpgi.00450.2002
    1. Griseri T, Asquith M, Thompson C, Powrie F. OX40 is required for regulatory T cell-mediated control of colitis. J Exp Med. 2010;207:699–709. doi:10.1084/jem.20091618
    1. Bell RB, Leidner RS, Crittenden MR, et al. OX40 signaling in head and neck squamous cell carcinoma: overcoming immunosuppression in the tumor microenvironment. Oral Oncol. 2016;52:1–10. doi:10.1016/j.oraloncology.2015.11.009
    1. Guo Z, Wang X, Cheng D, et al. PD-1 blockade and OX40 triggering synergistically protects against tumor growth in a murine model of ovarian cancer. PLoS One. 2014;9:e89350. doi:10.1371/journal.pone.0089350
    1. Martins MR, Santos RLD, Jatahy KDN, et al. Could OX40 agonist antibody promote activation of the anti-tumor immune response in gastric cancer? J Surg Oncol. 2018;117:840–844. doi:10.1002/jso.25001
    1. Lai C, August S, Albibas A, et al. OX40+ regulatory T cells in cutaneous squamous cell carcinoma suppress effector T-cell responses and associate with metastatic potential. Clin Cancer Res. 2016;22:4236–4248. doi:10.1158/1078-0432.ccr-15-2614
    1. Hamidinia M, Ghafourian Boroujerdnia M, Talaiezadeh A, Solgi G, Taghdiri M, Khodadadi A. Concomitant increase of OX40 and FOXP3 transcripts in peripheral blood of patients with breast cancer. Iran J Immunol. 2013;10:22–30. doi:IJIv10i1A3
    1. Weixler B, Cremonesi E, Sorge R, et al. OX40 expression enhances the prognostic significance of CD8 positive lymphocyte infiltration in colorectal cancer. Oncotarget. 2015;6:37588–37599. doi:10.18632/oncotarget.5940
    1. Zhang P, Tu GH, Wei J, et al. Ligand-Blocking and Membrane-Proximal Domain Targeting Anti-OX40 Antibodies Mediate Potent T Cell-Stimulatory and Anti-Tumor Activity. Cell Rep. 2019;27:3117–3123.e5. doi:10.1016/j.celrep.2019.05.027
    1. Aspeslagh S, Postel-Vinay S, Rusakiewicz S, Soria J-C, Zitvogel L, Marabelle A. Rationale for anti-OX40 cancer immunotherapy. Eur J Cancer. 2016;52:50–66. doi:10.1016/j.ejca.2015.08.021
    1. Buchan SL, Rogel A, Al-Shamkhani A. The immunobiology of CD27 and OX40 and their potential as targets for cancer immunotherapy. Blood. 2018;131:39–48. doi:10.1182/blood-2017-07-741025
    1. Curti BD, Kovacsovics-Bankowski M, Morris N, et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res. 2013;73:7189–7198. doi:10.1158/0008-5472.CAN-12-4174
    1. Foote JB, Kok M, Leatherman JM, et al. A STING agonist given with OX40 receptor and PD-L1 modulators primes immunity and reduces tumor growth in tolerized mice. Blood. 2017;5:468–479. doi:10.1182/blood-2017-07-741025; 10.1158/2326-6066.cir-16-0284.
    1. Moran AE, Kovacsovics-Bankowski M, Weinberg AD. The TNFRs OX40, 4-1BB, and CD40 as targets for cancer immunotherapy. Curr Opin Immunol. 2013;25:230–237. doi:10.1016/j.coi.2013.01.004
    1. Sanmamed MF, Pastor F, Rodriguez A, et al. Agonists of co-stimulation in cancer immunotherapy directed against CD137, OX40, GITR, CD27, CD28, and ICOS. Semin Oncol. 2015;42:640–655. doi:10.1053/j.seminoncol.2015.05.014
    1. Weinberg AD, Rivera MM, Prell R, et al. Engagement of the OX-40 receptor in vivo enhances antitumor immunity. J Immunol. 2000;164:2160–2169. doi:10.4049/jimmunol.164.4.2160
    1. Kjaergaard J, Tanaka J, Kim JA, Rothchild K, Weinberg A, Shu S. Therapeutic efficacy of OX-40 receptor antibody depends on tumor immunogenicity and anatomic site of tumor growth. Cancer Res. 2000;60:5514–5521.
    1. Morris A, Vetto JT, Ramstad T, et al. Induction of anti-mammary cancer immunity by engaging the OX-40 receptor in vivo. Breast Cancer Res Treat. 2001;67:71–80.
    1. Petty JK, He K, Corless CL, Vetto JT, Weinberg AD. Survival in human colorectal cancer correlates with expression of the T-cell costimulatory molecule OX-40 (CD134). Am J Surg. 2002;183:512–518. doi:10.1016/s0002-9610(02)00831-0
    1. Andarini S, Kikuchi T, Nukiwa M, et al. Adenovirus vector-mediated in vivo gene transfer of OX40 ligand to tumor cells enhances antitumor immunity of tumor-bearing hosts. Cancer Res. 2004;64:3281–3287.
    1. Song A, Tang X, Harms KM, Croft M. OX40 and Bcl-xL promote the persistence of CD8 T cells to recall tumor-associated antigen. J Immunol. 2005;175:3534–3541. doi:10.4049/jimmunol.175.6.3534
    1. Gough MJ, Ruby CE, Redmond WL, Dhungel B, Brown A, Weinberg AD. OX40 agonist therapy enhances CD8 infiltration and decreases immune suppression in the tumor. Cancer Res. 2008;68:5206–5215. doi:10.1158/0008-5472.CAN-07-6484
    1. Pham Minh N, Murata S, Kitamura N, et al. In vivo antitumor function of tumor antigen-specific CTLs generated in the presence of OX40 co-stimulation in vitro. Int J Cancer. 2018;142:2335–2343. doi:10.1002/ijc.31244
    1. Assudani DP, Ahmad M, Li G, Rees RC, Ali SA. Immunotherapeutic potential of DISC-HSV and OX40L in cancer. Cancer Immunol Immunother. 2006;55:104–111. doi:10.1007/s00262-005-0004-y
    1. Zaini J, Andarini S, Tahara M, et al. OX40 ligand expressed by DCs costimulates NKT and CD4+ Th cell antitumor immunity in mice. J Clin Invest. 2007;117:3330–3338. doi:10.1172/JCI32693
    1. Redmond WL, Linch SN, Kasiewicz MJ. Combined targeting of costimulatory (OX40) and coinhibitory (CTLA-4) pathways elicits potent effector T cells capable of driving robust antitumor immunity. Cancer Immunol Res. 2014;2:142–153. doi:10.1158/2326-6066.CIR-13-0031-T
    1. Linch SN, Kasiewicz MJ, McNamara MJ, Hilgart-Martiszus IF, Farhad M, Redmond WL. Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice. Proc Natl Acad Sci U S A. 2016;113:E319–E327. doi:10.1073/pnas.1510518113
    1. Berrong Z, Mkrtichyan M, Ahmad S, et al. Antigen-specific antitumor responses induced by OX40 agonist are enhanced by the IDO inhibitor indoximod. Cancer Immunol Res. 2018;6:201–208. doi:10.1158/2326-6066.CIR-17-0223
    1. Jahan N, Talat H, Curry WT. Agonist OX40 immunotherapy improves survival in glioma-bearing mice and is complementary with vaccination with irradiated GM-CSF-expressing tumor cells. Neuro-oncology. 2018;20:44–54. doi:10.1093/neuonc/nox125
    1. Virani NA, Thavathiru E, McKernan P, Moore K, Benbrook DM, Harrison RG. Anti-CD73 and anti-OX40 immunotherapy coupled with a novel biocompatible enzyme prodrug system for the treatment of recurrent, metastatic ovarian cancer. Cancer Lett. 2018;425:174–182. doi:10.1016/j.canlet.2018.03.027
    1. Chikuma S. CTLA-4, an essential immune-checkpoint for T-cell activation. Curr Top Microbiol Immunol. 2017;410:99–126. doi:10.1007/82_2017_61
    1. Chen X, Shao Q, Hao S, et al. CTLA-4 positive breast cancer cells suppress dendritic cells maturation and function. Oncotarget. 2017;8:13703–13715. doi:10.18632/oncotarget.14626
    1. Shi L, Meng T, Zhao Z, et al. CRISPR knock out CTLA-4 enhances the anti-tumor activity of cytotoxic T lymphocytes. Gene. 2017;636:36–41. doi:10.1016/j.gene.2017.09.010
    1. van Hooren L, Sandin LC, Moskalev I, et al. Local checkpoint inhibition of CTLA-4 as a monotherapy or in combination with anti-PD1 prevents the growth of murine bladder cancer. Eur J Immunol. 2017;47:385–393. doi:10.1002/eji.201646583
    1. Zhao Y, Yang W, Huang Y, Cui R, Li X, Li B. Evolving roles for targeting CTLA-4 in cancer immunotherapy. Cell Physiol Biochem. 2018;47:721–734. doi:10.1159/000490025
    1. Selby MJ, Engelhardt JJ, Quigley M, et al. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol Res. 2013;1:32–42. doi:10.1158/2326-6066.cir-13-0013
    1. Subrahmanyam PB, Dong Z, Gusenleitner D, et al. Distinct predictive biomarker candidates for response to anti-CTLA-4 and anti-PD-1 immunotherapy in melanoma patients. J Immunother Cancer. 2018;6:18. doi:10.1186/s40425-018-0328-8
    1. Wang B, Qin L, Ren M, Sun H. Effects of combination of anti-CTLA-4 and anti-PD-1 on gastric cancer cells proliferation, apoptosis and metastasis. Cell Physiol Biochem. 2018;49:260–270. doi:10.1159/000492876
    1. Wei SC, Levine JH, Cogdill AP, et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell. 2017;170:1120–1133.e17. doi:10.1016/j.cell.2017.07.024
    1. Goncalves-Lopes RM, Lima NF, Carvalho KI, Scopel KKG, Kallás EG, Ferreira MU. Surface expression of inhibitory (CTLA-4) and stimulatory (OX40) receptors by CD4(+) regulatory T cell subsets circulating in human malaria. Microbes Infect. 2016;18:639–648. doi:10.1016/j.micinf.2016.06.003
    1. Montler R, Bell RB, Thalhofer C, et al. OX40, PD-1 and CTLA-4 are selectively expressed on tumor-infiltrating T cells in head and neck cancer. Clin Transl Immunol. 2016;5:e70. doi:10.1038/cti.2016.16
    1. Redmond WL, Linch SN, Kasiewicz MJ. Combined targeting of costimulatory (OX40) and coinhibitory (CTLA-4) pathways elicits potent effector T cells capable of driving robust antitumor immunity. Proc Natl Acad Sci U S A. 2014;2:142–153. doi:10.1073/pnas.1510518113; 10.1158/2326-6066.cir-13-0031-t.
    1. Linch SN, Redmond WL. Combined OX40 ligation plus CTLA-4 blockade: more than the sum of its parts. Oncoimmunology. 2014;3:e28245. doi:10.4161/onci.28245
    1. Messenheimer DJ, Jensen SM, Afentoulis ME, et al. Timing of PD-1 blockade is critical to effective combination immunotherapy with anti-OX40. Clin Cancer Res. 2017;23:6165–6177. doi:10.1158/1078-0432.CCR-16-2677
    1. Chamoto K, Al-Habsi M, Honjo T. Role of PD-1 in immunity and diseases. Curr Top Microbiol Immunol. 2017;410:75–97. doi:10.1007/82_2017_67
    1. Kuol N, Stojanovska L, Nurgali K, Apostolopoulos V. PD-1/PD-L1 in disease. Immunotherapy. 2018;10:149–160. doi:10.2217/imt-2017-0120
    1. Salmaninejad A, Khoramshahi V, Azani A, et al. PD-1 and cancer: molecular mechanisms and polymorphisms. Immunogenetics. 2018;70:73–86. doi:10.1007/s00251-017-1015-5
    1. Shrimali RK, Ahmad S, Verma V, et al. Concurrent PD-1 blockade negates the effects of OX40 agonist antibody in combination immunotherapy through inducing T-cell apoptosis. Cancer Immunol Res. 2017;5:755–766. doi:10.1158/2326-6066.CIR-17-0292
    1. Buchan S, Manzo T, Flutter B, et al. OX40- and CD27-mediated costimulation synergizes with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence. J Immunol. 2015;194:125–133. doi:10.4049/jimmunol.1401644
    1. Jacobi FJ, Wild K, Smits M, et al. OX40 stimulation and PD-L1 blockade synergistically augment HBV-specific CD4 T cells in patients with HBeAg-negative infection. J Hepatol. 2019;70:1103–1113. doi:10.1016/j.jhep.2019.02.016
    1. Dawicki W, Bertram EM, Sharpe AH, Watts TH. 4-1BB and OX40 act independently to facilitate robust CD8 and CD4 recall responses. J Immunol. 2004;173:5944–5951. doi:10.4049/jimmunol.173.10.5944
    1. Cannons JL, Lau P, Ghumman B, et al. 4-1BB ligand induces cell division, sustains survival, and enhances effector function of CD4 and CD8 T cells with similar efficacy. J Immunol. 2001;167:1313–1324. doi:10.4049/jimmunol.167.3.1313
    1. Chester C, Ambulkar S, Kohrt HE. 4-1BB agonism: adding the accelerator to cancer immunotherapy. Cancer Immunol Immunother. 2016;65:1243–1248. doi:10.1007/s00262-016-1829-2
    1. Chester C, Sanmamed MF, Wang J, Melero I. Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. J Biol Chem. 2018;131:49–57. doi:10.1074/jbc.M117.814905; 10.1182/blood-2017-06-741041.
    1. Lu Y, Li C, Du S, et al. 4-1BB signaling promotes alveolar macrophages-mediated pro-fibrotic responses and crystalline silica-induced pulmonary fibrosis in mice. Front Immunol. 2018;9:1848. doi:10.3389/fimmu.2018.01848
    1. Oh HS, Choi BK, Kim YH, et al. 4-1BB signaling enhances primary and secondary population expansion of CD8+ T cells by maximizing autocrine IL-2/IL-2 receptor signaling. PLoS One. 2015;10:e0126765. doi:10.1371/journal.pone.0126765
    1. Bartkowiak T, Curran MA. 4-1BB agonists: multi-potent potentiators of tumor immunity. Front Oncol. 2015;5:117. doi:10.3389/fonc.2015.00117
    1. Sakellariou-Thompson D, Forget M-A, Creasy C, et al. 4-1BB agonist focuses CD8(+) tumor-infiltrating T-cell growth into a distinct repertoire capable of tumor recognition in pancreatic cancer. Clin Cancer Res. 2017;23:7263–7275. doi:10.1158/1078-0432.ccr-17-0831
    1. Munks MW, Mourich DV, Mittler RS, Weinberg AD, Hill AB. 4-1BB and OX40 stimulation enhance CD8 and CD4 T-cell responses to a DNA prime, poxvirus boost vaccine. Immunology. 2004;112:559–566. doi:10.1111/j.1365-2567.2004.01917.x
    1. Hendriks J, Xiao Y, Rossen JWA, et al. During viral infection of the respiratory tract, CD27, 4-1BB, and OX40 collectively determine formation of CD8+ memory T cells and their capacity for secondary expansion. J Immunol. 2005;175:1665–1676. doi:10.4049/jimmunol.175.3.1665
    1. Lee SJ, Myers L, Muralimohan G, et al. 4-1BB and OX40 dual costimulation synergistically stimulate primary specific CD8 T cells for robust effector function. J Immunol. 2004;173:3002–3012. doi:10.4049/jimmunol.173.5.3002
    1. Lee SW, Park Y, Song A, Cheroutre H, Kwon BS, Croft M. Functional dichotomy between OX40 and 4-1BB in modulating effector CD8 T cell responses. J Immunol. 2006;177:4464–4472. doi:10.4049/jimmunol.177.7.4464

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi