Intratumoral antigen signaling traps CD8+ T cells to confine exhaustion to the tumor site.

Immunotherapy advances have been hindered by difficulties in tracking the behaviors of lymphocytes after antigen signaling. Here, we assessed the behavior of T cells active within tumors through the development of the antigen receptor signaling reporter (AgRSR) mouse, fate-mapping lymphocytes responding to antigens at specific times and locations. Contrary to reports describing the ready egress of T cells out of the tumor, we find that intratumoral antigen signaling traps CD8⁺ T cells in the tumor. These clonal populations expand and become increasingly exhausted over time. By contrast, antigen-signaled regulatory T cell (T_reg) clonal populations readily recirculate out of the tumor. Consequently, intratumoral antigen signaling acts as a gatekeeper to compartmentalize CD8⁺ T cell responses, even within the same clonotype, thus enabling exhausted T cells to remain confined to a specific tumor tissue site. Editor's summary: An understanding of how T cells behave after antigen signaling is critical to improving immunotherapies. Takahashi et al. developed the antigen receptor signaling reporter (AgRSR) mice to fate-map T cells responding to antigen signals. In tumors, they showed that antigen engagement caused clonally expanded CD8 T cells to be retained within tumors, resulting in T cell exhaustion. Whereas antigen engagement of regulatory T cells (T_regs) within tumors similarly induced clonal expansion, T_regs were able to recirculate. These results provide insight into T cell behaviors that may limit antitumor responses and introduce a system for tracking adaptive immunity. —Christiana Fogg [ABSTRACT FROM AUTHOR]