Pre‐Encoded IFN‐I Sensitivity Exacerbates Memory T Cell Senescence in Solid Tumors

Abstract Solid tumors often suppress antitumor immune responses by promoting various dysfunctional CD8+ T cell states, which limit the effectiveness of T‐cell‐based immunotherapy. However, the mechanisms that promote these states have not been fully characterized. It is demonstrated that spontaneous priming responses during tumor growth can produce memory T cell reservoirs that are conducive to poor proliferative responsiveness during boosting vaccination. Surprisingly, when type I interferon (IFN‐I) signaling is impeded, boosting vaccination can elicit robust proliferative responses from tumor‐primed memory T cells and promote tumor control. This is observed in multiple tumor types and target antigens. In contrast to conventional memory T cells, tumor‐primed memory T cells are unique in their pre‐encoded responsiveness to IFN‐I and show enrichment of pathways pertaining to DNA repair and cell cycle arrest. Tumor‐primed memory T cells up‐regulate p21 expression and blockade of either p21 or IFN‐I can alleviate this effect to improve their proliferative capacity during boosting vaccination. Characterization of tumor‐primed memory T cells revealed transcriptional and phenotypic features of cellular senescence, where higher senescence severity correlated with higher responsiveness to IFNα/β receptor blockade. Overall, IFN‐I hyperresponsiveness may be a unique feature of senescent tumor‐primed memory T cells that can exacerbate their dysfunction during cancer vaccination.