Abstract 3771: Splenic macrophages induce chemotherapy resistance via DNA damage repair
Authors: Houthuijzen Julia M. , Daenen Laura G.M. , Roodhart Jeanine M.L. , Govaert Klaas M. , Smith Michelle E. , Thomale Juergen , Sadatmand Sahar J. , Rosing Hilde , Kruse Fabian , Rooijen Nico van , Beijnen Jos H. , Borst Piet , Rottenberg Sven , Haribabu Bodduluri , Voest Emile E. 
Published: May 2015

Abstract
The development of resistance to chemotherapy is one of the most important obstacles to continued effective treatment of cancer in patients. We recently identified an important network that is responsible for reversible systemic resistance to chemotherapy. Mesenchymal stem cells (MSCs), activated by chemotherapy, secrete two specific polyunsaturated fatty acids that confer resistance to a broad spectrum of anti-cancer agents. These two distinct platinum-induced polyunsaturated fatty acids (PIFAs), 12-S-keto-5,8,10-heptadecatrienoic acid (KHT) and 4,7,10,13-hexadecatetraenoic acid (16:4(n-3)), can independently induce chemotherapy resistance at picomolar concentrations. Here we show that these PIFAs do not induce resistance to the tumor cells directly but rather function systemically via F4/80+/CD11blow/Ly6G- splenocytes to enhance DNA damage repair within tumors. We found that the PIFAs only induce resistance against DNA damaging agents but not against non-DNA damaging chemotherapeutics. When comparing tumors from cisplatin and PIFAs treated mice with cisplatin alone treated mice we found overall less DNA damage and a quicker restoration of DNA damage. In BRCA1-/-/p53-/- mice lacking homologous recombination, PIFAs were unable induce chemotherapy resistance.
Several lines of evidence identified F4/80+/CD11blow/Ly6G- splenocytes as key mediators within this mechanism of systemic chemoresistance. First, PIFAs were unable to induce resistance in splenectomized tumor-bearing mice. Second, administration of conditioned medium from splenocytes (sCM) activated by the PIFAs to splenectomized mice was able to re-introduce systemic chemotherapy resistance in various mouse models (mean tumor volume in mm3 8 days after treatment ± SEM control: 290.7 ± 33.4, cisplatin: 118.2 ± 8.9 and cisplatin + sCM: 261.1 ± 29.7). Third, analysis of the different cell types present in the spleen indicated that F4/80+/CD11blow expressing cells were able to induce systemic resistance in splenectomized mice. Finally, administration of liposomal clodronate to tumor-bearing mice treated with chemotherapy and PIFAs was able to inhibit induction of resistance. Given the fact that 12-S-HHT is a natural ligand of the leukotriene B4 receptor 2 (BLT2) we investigated if signaling via BLT2 is responsible for 12-S-HHT-induced chemoresistance. Both genetic loss of BLT2 or inhibition of BLT2 using LY255283 was able to prevent 12-S-HHT-mediated chemoresistance. Taken together, our findings provide a novel role for the spleen in inducing a systemic protection against chemotherapy via enhancing DNA damage repair.
Citation Format: Julia M. Houthuijzen, Laura G.M, Daenen, Jeanine M.L. Roodhart, Klaas M. Govaert, Michelle E. Smith, Juergen Thomale, Sahar J. Sadatmand, Hilde Rosing, Fabian Kruse, Nico van Rooijen, Jos H. Beijnen, Piet Borst, Sven Rottenberg, Bodduluri Haribabu, Emile E. Voest. Splenic macrophages induce chemotherapy resistance via DNA damage repair. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3771. doi:10.1158/1538-7445.AM2014-3771