Faculty of Medical and Health Sciences


Re-polarising the Stromal Microenvironment from Pro-Tumour to Anti-Tumour

DMXAA

Immune cells within the tumour stroma can adopt either a pro-tumour or an anti-tumour phenotype depending on the cytokine milieu in local microenvironment. We have been investigating small molecule cytokine inducers that can create the appropriate microenvironment to re-polarise the neutrophil and macrophage infiltrates in tumours.  DMXAA, developed at the ACSRC initially as a vascular disrupting agent, we have shown, activates the production of a panel of cytokines within the tumour (1-3) resulting in re-polarisation of the macrophages from M2 (pro-tumour) to M1 (anti-tumour) phenotype (4, 5).  Efforts directed at identifying the signalling pathway(s) and molecular target(s) involved in cytokine induction by DMXAA indicate that multiple pathways and targets are involved, including NF-kB (6), the TBK1-IRF-3 signalling axis (7), NOD (8), MAP kinases (9), and redox signalling (10). Recent evidence has pointed to the mammalian endoplasmic reticulum protein, STING (stimulator of interferon genes), a frontline sensor of the innate immune system, as being a key receptor in murine macrophages for DMXAA. Despite 89% homology in the murine and human homologues, DMXAA binds only to murine STING, providing a salient explanation for the species-selectivity in the activity of DMXAA. We recently described DMXAA analogues that stimulated IL-8, IL-6 and TNF production in human macrophages (11). The ability of these ‘ human selective’  XAA analogues to re-polarize murine or human macrophages from M2 to M2 phenotype, and the key signalling pathways involved in this process are currently being investigated.

References


1. Henare K,  Wang L, Wang L-CS, Thomsen L, Tijono S, Chen C-JJ, Winkler S, Dunbar PR, Print C, Ching L-M. Dissection of stromal and cancer cell-derived signals in melanoma xenografts before and after treatment with DMXAA. Bri J Cancer, 106, 1134-1147, 2012.

2. Wang, L-CS, Thomsen, L, Sutherland, R, Reddy, C, Tijono, S, Chen, C-JJ, Angel, KE, Dunbar, PR, Ching L-M. Neutrophil influx and chemokine production during the early phases of the anti-tumor response to the vascular disrupting agent DMXAA (ASA404).Neoplasia, 11, 793-803, 2009.

4. Jassar, A.S., Suzuki, E., Kapoor, V., Sun, J., Silverberg, M.B., Cheung, L., Burdick, M.D., Streiter, R.M., Ching, L-M., Kaiser, L.R., Albelda, S.M. Activation of tumor-associated macrophages by the vascular disrupting agent 5,6 dimethylxanthenone-4-acetic acid (DMXAA) induces an effective CD8+ T-cell-mediated anti-tumor immune response in immunogenic and non-immunogenic murine models of lung cancer and mesothelioma. Cancer Res, 65, 11752-11761, 2005.

5. Fridlender ZG, Jassar A, Mishalian I, Wang L-CS, Kapoor V, Cheng G, Sun J, Singhal S, Levy L, Albelda SM. Using macrophage activation to augment immunotherapy of established tumours. , Bri J Cancer, 108, 1288-1297, 2013.

6. Woon, S-T, Zwain, S, Schooltink, M. A., Newth, A. L., Baguley, B. C., Ching, L-M. NF-kB activation in vivo in both host and tumour cells by the antivascular agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA).  Eur J Cancer, 39, 1176-1183, 2003.

7. Roberts, ZJ, Goutagny, N, Perera, P-Y, Fitzgerald, KA, Kato, H, Kumar, H, Kawai, T, Akira, S, Savan, R, van Echo D, Young, HA,Ching, L-M, Vogel, SN. The Chemotherapeutic agent 5,6-dimethylxanthenone-4-acetic acid, potently and specifically activates the TBK1-IRF-3 signalling axis. J Exp Med 204, 1559-1569, 2007.

8. Cheng G, Sun J, Fridlender ZG, Wang L-CS, Ching L-M, Albelda SM. Activation of the NOD signalling pathway by a non-bacterially derived drug: 5,6-dimethylxanthenone-4-acetic acid (DMXAA, Vadimezan). J Biol Chem, 285, 10553-10562,2010.

9. Sun J, Wang LS, Fridlender Z G, Kapoor V, Cheng, G, Ching L-M, Albelda, S. M. Activation of mitogen-activated protein kinases by 5,6-dimethylxanthenone- 4-acetic acid (DMXAA) plays an important role in macrophage stimulation. Biochem Pharmacol, 82, 1175-1185, 2011.

10. Brauer R, Wang L-CS, Woon S-T, Bridewell DJA, Henare K, Malinger D, Tijono SM, Palmer BD, Vogel SN, Kieda C, Ching L-M. Labelling of oxidizable proteins with a photoactivatable analogue of the anti-tumor agent DMXAA: evidence for redox signalling in its mode of action. Neoplasia, 12, 755-765, 2010.

11. Tijono SM, Guo K, Henare K, Palmer BD, Wang L-CS, Albelda SM, Ching L-M. Identification of human-selective analogues of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Bri  J Cancer, 108, 1306-1315 2013.