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

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.