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Background: CD137L is expressed on antigen presenting cells and CD137/CD137L interaction co-stimulates activation and proliferation of CD137 expressing T cells. CD137L expression has also been detected on various cancer cells. While signaling in immune cells showed both inhibiting and activating effects the impact of CD137L induction on tumor cells is poorly understood. In this study, the expression of CD137 and CD137L and the effects of CD137L activation were analyzed in human colorectal cancer (CRC). Methods: Expression of CD137 and CD137L was examined in human colon cancer cell lines HT29, SW480 and SW620 treated with or without hypoxia using RT-qPCR, Western blot and FACS analysis. Its differentiated expression was further analyzed in human CRCs by immunofluorescent double-staining. To dissect the effects of CD137L activation on cancer cells, MTS proliferation assays were additionally performed. Results: All three human colon cancer cell lines demonstrated high cellular (FACS) and protein (Western Blot) CD137L expression. CD137 was found only in SW480 cells at weak expression. Additionally, both CD137 and CD137L were significantly upregulated in cells treated with hypoxia. In human CRCs both CD137 and CD137L expressing tumor cells were detected by immunofluorescent double-staining. Interestingly, activation of CD137L by immobilized CD137-Fc resulted in reduced cancer cell proliferation compared to IgG1-Fc controls. Conclusion: Our results demonstrate tumor cell mediated expression of the costimulatory molecule CD137 and its ligand CD137L in both colon cancer cell lines and human colorectal cancer. Moreover, CD137L reverse signaling was found to reduce cancer cell proliferation in vitro. Based on these data, the CD137/CD137L signaling pathway seems to present a promising target for cancer therapy in CRC. Note: This abstract was not presented at the meeting. Citation Format: Tanja Grimmig, Simone Callies, Hannes Naegele, Martin Wagner, Romana Moench, Buelent Polat, Christoph-Thomas Germer, Martin Gasser, Ana Maria Waaga-Gasser. Activation of CD137/CD137L results in reduced tumor cell proliferation in human colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5616. doi:10.1158/1538-7445.AM2017-5616