AUTHOR=Chia Tzu-Yi , Billingham Leah K. , Boland Lauren , Katz Joshua L. , Arrieta Victor A. , Shireman Jack , Rosas Aurora-Lopez , DeLay Susan L. , Zillinger Kaylee , Geng Yuheng , Kruger Jeandre , Silvers Caylee , Wang Hanxiang , Vazquez Cervantes Gustavo Ignacio , Hou David , Wang Si , Wan Hanxiao , Sonabend Adam , Zhang Peng , Lee-Chang Catalina , Miska Jason 

TITLE=The CXCL16-CXCR6 axis in glioblastoma modulates T-cell activity in a spatiotemporal context

JOURNAL=Frontiers in Immunology

VOLUME=Volume 14 - 2023

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1331287

DOI=10.3389/fimmu.2023.1331287

ISSN=1664-3224

ABSTRACT=A crucial facet of GBM pathobiology is its profound ability to induce immunosuppression within the tumor microenvironment, which is primarily orchestrated by immunosuppressive tumor-associated myeloid cells (TAMCs). Myeloid cells are pivotal in shaping the GBM microenvironment and modulating immune responses, and direct physical interactions with effector immune cells play a critical role in these processes. While these interactions can foster antitumor immunity by presenting tumor antigens to T cells, they can also promote immunosuppression by inhibiting effector immune cell functions. Our study highlights the critical role of the CXCR6/CXCL16 axis in T-cell myeloid interactions within GBM tissues. Specifically, our data revealed that CXCL16 surface expression is limited to TAMCs, whereas microglia release CXCL16 as a cytokine. Consequently, T cells predominantly engage with TAMCs, leading to impaired T-cell function within the tumor environment. Conversely, our findings also underscore the essential role of CXCR6 expression in Tcell activation and initial migration to tumor tissues. Thus, the CXCL16-CXCR6 axis has dualistic characteristics: it facilitates the early stages of the T-cell immune response, facilitating T-cell infiltration into tumors, but once inside the tumor, it promotes immunosuppression. These results suggest that while targeting the CXCL16/CXCR6 axis has therapeutic potential in GBM, carefully considering the timing and context of intervention is crucial.