OX40 (CD134)

Overview

  • OX40, a tumor necrosis factor receptor superfamily (TNFRSF) member, is a costimulatory receptor that is transiently upregulated on the surface of T-cell receptor (TCR)-activated T cells and is expressed at high levels on tumor resident regulatory T cells (Tregs). The OX40 ligand, OX40L, can be upregulated on antigen-presenting dendritic cells.1,2
    • Optimal T-cell activation requires costimulatory signals.3
    • OX40/OX40L interactions on activated T cells dramatically increase the proliferation, differentiation, survival, effector function, memory formation, cytotoxic function, and cytokine production of those T cells.3,4
    • The primary signaling cascade in OX40-stimulated cells is via NF-κb activation and subsequent upregulation of antiapoptotic proteins.5
    • OX40/OX40L interactions on Tregs inhibit their ability to suppress cytotoxic T cells and prevent the TGF-β—mediated conversion of CD4+ T cells into Tregs.2,6
    • OX40-mediated bioactivity on other immune cell populations (ie, NK cells, B cells, neutrophils) may also contribute to immune system responses.7-10
  • The dual mechanism of action of OX40 agonism can result in conditions favorable to immune responses, where activated T cells increase in number and gain effector function, while the induction of Tregs is suppressed in the periphery.11,12

Implications in cancer

  • T-cell priming and activation followed by the trafficking and infiltration of T cells into tumors are critical steps in the anti-cancer immune response. Suboptimal T-cell activation to tumor-specific antigens and T-cell exhaustion may be significant barriers to an effective immune response.13
  • Agonism of OX40 may be a means to harness and enhance the natural immune effector mechanisms for tumor detection and elimination by increasing the proliferation, differentiation, survival, and cytotoxic activity of CD4+ and CD8+ T cells and impeding the induction and suppressive activity of Tregs.4,14
  • Ongoing clinical trials are evaluating OX40 agonism in combination with other agents for the treatment of various cancers.
  1. Evans DE, Prell RA, Thalhofer CJ, Hurwitz AA, Weinberg AD. Engagement of OX40 enhances antigen-specific CD4(+) T cell mobilization/memory development and humoral immunity: comparison of alphaOX-40 with alphaCTLA-4. J Immunol. 2001;167(12):6804-6811.
  2. Vu MD, Xiao X, Gao W, et al. OX40 costimulation turns off Foxp3+ Tregs. Blood. 2007;110(7):2501-2510.
  3. Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27(8):1492-1504.
  4. 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(24):7189-7198.
  5. Song J, So T, Croft M. Activation of NF-kappaB1 by OX40 contributes to antigen-driven T cell expansion and survival. J Immunol. 2008;180(11):7240-7248.
  6. Xiao X, Kroemer A, Gao W, Ishii N, Demirci G, Li XC. OX40/OX40L costimulation affects induction of Foxp3+ regulatory T cells in part by expanding memory T cells in vivo. J Immunol. 2008;181(5):3193-3201.
  7. Jensen SM, Maston LD, Gough MJ, et al. Signaling through OX40 enhances antitumor immunity. Semin Oncol. 2010;37(5):524-532.
  8. Baumann R, Yousefi S, Simon D, Russmann S, Mueller C, Simon HU. Functional expression of CD134 by neutrophils. Eur J Immunol. 2004;34(8):2268-2275.
  9. 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(11):3330-3338.
  10. 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(2):297-304.
  11. 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(13):5206-5215.
  12. Zhang X, Xiao X, Lan P, et al. OX40 costimulation inhibits Foxp3 expression and Treg induction via BATF3-dependent and independent mechanisms. Cell Rep. 2018;24(3):607-618.
  13. 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(1):125-133.
  14. Guo Z, Wang X, Cheng D, Xia Z, Luan M, Zhang S. PD-1 blockade and OX40 triggering synergistically protects against tumor growth in a murine model of ovarian cancer. PLoS One. 2014;9(2):e89350.

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