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Role of OX40 in T Cell Biology of Cancer and Infectious Disease

OX40, also known as gp34, CD134, or TNFRSF4, is a member of the TNF superfamily. It is primarily expressed on activated effector and regulatory CD4 and CD8 T cells; it can also be expressed by NKT cells, NK cells, and neutrophils in the immune system.1 It is a costimulatory molecule whose ligand, OX40L (CD252), is expressed by antigen presenting cells including dendritic cells.2 and macrophages3 Signaling via OX40 recruits TRAF2 and TRAF5 to activate the NFkB pathway, which is negatively regulated by TRAF3.4 OX40 is upregulated on newly activated T cells following engagement of the T cell receptor. Engagement of OX40 also promotes the formation of memory T cells, and reactivated T cells upregulate OX40 more quickly than do T cells activated for the first time.5 OX40 also promotes cell survival through maintenance of Bcl-xL, Bcl-2, and Akt levels, whereas lack of OX40 leads to apoptosis.1,6

Upregulation of OX40 is found in numerous inflammatory diseases. Constitutive engagement of OX40 results in autoimmune diseases including experimental autoimmune encephalomyelitis (a model of multiple sclerosis) and inflammatory bowel diseases including celiac disease, Crohn’s disease, and ulcerative colitis.7–9 Not only is expression of OX40 associated with these disease states, but blockade of OX40 in both experimental autoimmune encephalomyelitis.10 and inflammatory bowel disease11 ameliorates symptoms of the disease and lowers the levels inflammatory markers. OX40 expression is also found on alloreactive T cells in acute graft-versus-host disease, a severe side effect of bone marrow transplantation. These T cells are found throughout the body, in liver, skin, spleen, and lymph node of disease-affected hosts12 However, current therapies for these autoimmune diseases do not include OX40 blockade.

Conversely, targeting of OX40 has been tested in clinical trials for cancer. Inflammation in the cancer setting is indicative of an anti-tumor immune response, and OX40 expression on T cells in the tumor microenvironment is a marker of inflammation. OX40-expressing tumor-specific T cells have been found in the draining lymph nodes and/or tumor bed of melanoma, head and neck cancer.13, breast cancer14, and colorectal cancer15 In primary colorectal cancer patients, this pattern of OX40 expression is associated with increased survival.15 Several preclinical models have demonstrated that OX40 agonism in combination with checkpoint blockade immunotherapies including anti-4-1BB, anti-PD-L1, and anti-CTLA4, leads to increased survival.16 The first clinical trial using a OX40 agonist as a treatment for cancer began in 200617 and since then, over ten more trials using an OX40 agonist either alone or in combination have been approved. OX40 agonism has additionally been effective as in combination therapies for cancer when added to radiotherapy, chemotherapy, and immune activating therapies including IL-2 and TLR agonists.16

Fortis offers Rabbit anti-OX40/CD134 Recombinant Monoclonal Antibody [BLR042F] and its binding partner Rabbit anti-OX40L/TNFSF4 Recombinant Monoclonal Antibody [BLR165J] to meet your research needs.

Detection of human OX40/CD134 by immunohistochemistry.

Detection of human OX40/CD134 (red) by immunohistochemistry.

Detection of human OX40/CD134 by immunocytochemistry.

References

  1. Croft M, So T, Duan W, Soroosh P. The significance of OX40 and OX40L to T-cell biology and immune disease. Immunol Rev. 2009;229(1):173-191. doi:10.1111/j.1600-065X.2009.00766.x.
  2. 2. Ohshima Y, Tanaka Y, Tozawa H, Takahashi Y, Maliszewski C, Delespesse G. Expression and function of OX40 ligand on human dendritic cells. J Immunol. 1997;159(8):3838-3848.
  3. Weinberg AD, Vella AT, Croft M. OX-40: life beyond the effector T cell stage. Semin Immunol. 1998;10(6):471-480. doi:10.1006/smim.1998.0146.
  4. Kawamata S, Hori T, Imura A, Takaori-Kondo A, Uchiyama T. Activation of OX40 signal transduction pathways leads to tumor necrosis factor receptor-associated factor (TRAF) 2- and TRAF5-mediated NF-kappaB activation. J Biol Chem. 1998;273(10):5808-5814. doi:10.1074/JBC.273.10.5808.
  5. Gramaglia I, Jember A, Pippig SD, Weinberg AD, Killeen N, Croft M. The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion. J Immunol. 2000;165(6):3043-3050.
  6. 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(3):445-455. 
  7. Murata K, Nose M, Ndhlovu LC, Sato T, Sugamura K, Ishii N. Constitutive OX40/OX40 ligand interaction induces autoimmune-like diseases. J Immunol. 2002;169(8):4628-4636.
  8. Weinberg AD, Wallin JJ, Jones RE, et al. Target organ-specific up-regulation of the MRC OX-40 marker and selective production of Th1 lymphokine mRNA by encephalitogenic T helper cells isolated from the spinal cord of rats with experimental autoimmune encephalomyelitis. J Immunol. 1994;152(9):4712-4721.
  9. Stüber E, Büschenfeld A, Lüttges J, Von Freier A, Arendt T, Fölsch UR. The expression of OX40 in immunologically mediated diseases of the gastrointestinal tract (celiac disease, Crohn’s disease, ulcerative colitis). Eur J Clin Invest. 2000;30(7):594-599. 
  10. Weinberg AD, Wegmann KW, Funatake C, Whitham RH. Blocking OX-40/OX-40 ligand interaction in vitro and in vivo leads to decreased T cell function and amelioration of experimental allergic encephalomyelitis. J Immunol. 1999;162(3):1818-1826.
  11. Higgins LM, McDonald SA, Whittle N, Crockett N, Shields JG, MacDonald TT. Regulation of T cell activation in vitro and in vivo by targeting the OX40-OX40 ligand interaction: amelioration of ongoing inflammatory bowel disease with an OX40-IgG fusion protein, but not with an OX40 ligand-IgG fusion protein. J Immunol. 1999;162(1):486-493.
  12. Tittle T V, Weinberg AD, Steinkeler CN, Maziarz RT. Expression of the T-cell activation antigen, OX-40, identifies alloreactive T cells in acute graft-versus-host disease. Blood. 1997;89(12):4652-4658.
  13. Vetto JT, Lum S, Morris A, et al. Presence of the T-cell activation marker OX-40 on tumor infiltrating lymphocytes and draining lymph node cells from patients with melanoma and head and neck cancers. Am J Surg. 1997;174(3):258-265.
  14. Ramstad T, Lawnicki L, Vetto J, Weinberg A. Immunohistochemical analysis of primary breast tumors and tumor-draining lymph nodes by means of the T-cell costimulatory molecule OX-40. Am J Surg. 2000;179(5):400-406.
  15. 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(5):512-518.
  16. Linch SN, McNamara MJ, Redmond WL. OX40 Agonists and Combination Immunotherapy: Putting the Pedal to the Metal. Front Oncol. 2015;5:34. doi:10.3389/fonc.2015.00034.
  17. Weinberg AD, Morris NP, Kovacsovics-Bankowski M, Urba WJ, Curti BD. Science gone translational: the OX40 agonist story. Immunol Rev. 2011;244(1):218-231. doi:10.1111/j.1600-065X.2011.01069.x.