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. We demonstrate 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 IFN-I signaling is impeded, boosting vaccination can elicit robust proliferative responses from tumor-primed memory T cells and promote tumor control. This was 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 IFNAR 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. We used whole transcriptome arrays (Clariom S) to analyze the state of dysfunction when comparing VP-TM, TP-TM(B16), an TP-TM(MC38) C57BL/6 mice were challenged i.d. with B16-gp33/MC38-gp33 tumors in order to generate TP-TMB16/ TP-TMMC38 or acutely infected i.v. with LCMV in order to generate VP-TM. Memory T cells were isolated from secondary lymphoid tissue and sorted based on gp33H2DbTet+ CD8+ staining. RNA was extracted from purified cells for whole transcriptome analysis (ClariomS)