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

Sci Immunol. 2024 May 24;9(95):eade2094. doi: 10.1126/sciimmunol.ade2094. Epub 2024 May 24.

Abstract

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 (Treg) 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.

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology
  • CD8-Positive T-Lymphocytes* / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasms / immunology
  • Signal Transduction* / immunology

Substances

  • Antigens, Neoplasm