Abstract R-Ras belongs the RAS superfamily of small GTP-binding proteins implicated in cell adhesion signaling. Unlike classical Ras proteins, R-Ras is not activated by growth factor receptors. Rather, its GTPase activity is modulated by molecules implicated in cell-cell adhesion including semaphorins and notch. Using an R-Ras knockout mouse strain, we have previously reported that R-Ras is required for murine Dendritic cell functions. Further characterization of this mouse strain revealed reduced cellularity of peripheral lymph nodes (PLNs) by 40% with T cell regions in the paracortex in which high endothelial venules (HEV) resided were less prominent when compared with wild-type (WT) mice. Consistently, immunohistological analysis for MECA-79, a marker of mature HEV, showed a 3- to 4-fold decrease in staining intensity. This is correlated with a 30-40% reduction in the number of CD62L+ CD4 and CD8 T cells in PLNs. Furthermore, R-Ras null T cells had reduced proliferative and homing capacity when compared with WT. More importantly, we demonstrated for the first time that the chemokine CCL21 was able to stimulate the GTP-loading of R-Ras within 15 seconds of addition. Indeed, R-Ras null T-cells displayed reduced binding to soluble ICAM-1 as well as to 2H-11 endothelial cells. To explore the role of R-Ras in anti-tumor immunity, B16/F10 melanoma cells were injected subcutaneously to WT and R-Ras null mice. In addition, a mouse breast tumor model was generated ineither WT or R-Ras-null genetic background. Tumor development and the number of infiltrating immune cells were analyzed to examine if R-Ras was involved in either anti- or pro-tumor immune responses. This work was supported by NIH CA78509 (AMC), MH59771 (AMC). MY was supported by Hong Kong PhD Fellowship Scheme (PF12-13584) and AMC was supported by the Lo Kwee-Seong Seed Fund, and a General Research Fund Grant, 14120915, from Hong Kong University Grants Committee. Note: This abstract was not presented at the meeting. Citation Format: Andrew M. Chan, Xiaocai Yan, Wai Nam Liu, Mingfei Yan. R-Ras is required for T cell trafficking in high endothelial venues and implicated in anti-tumor immunity [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 3711. doi:10.1158/1538-7445.AM2017-3711