Introduction/Rationale: Exhaustion of CD8 T-cells limits immunotherapy outcomes. Targeting the immune checkpoint PD-1 temporally relieve some functional constraints on exhausted CD8 T-cells (TEX) but most patients fail to achieve durable benefits. The contribution of cell-intrinsic regulatory processes to the limited durability of TEX responses remains poorly defined.
Methods: To address this gap, we took advantage of the murine Lymphocytic Choriomeningitis Virus (LCMV) model and performed a pseudo-temporal analysis of TEX cell responses to PD-1 therapy. This analysis captured the cellular, functional, and transcriptional dynamics underlying TEX responses across the whole duration of PD-1 therapy.
Results: Notably, PD-1 blockade had limited impact on TEX functions but rather triggers a single proliferative wave, initiated at the TEXprog stage that perpetrates in downstream subsets, resulting in a temporal numerical burst of “effector-like” TEX intermediate (TEXint) cells. Importantly, we discovered that TEXprog cells fail to maintain this proliferative response and develop a cell-intrinsic resistance to further division. This observation revealed the existence of self-regulatory mechanisms imposing a temporal limitation to the responsiveness of TEXprog cells to PD-1 therapy. Using longitudinal scRNAseq analysis, we uncovered important transcriptional changes in these cells and notably an increase activity of several members of the Interferon Responsive Factor (IRF) family of transcription factors, implicating type I interferon signals in modulating the biology of TEXprog cells upon PD-1 therapy. Temporal blockade of type I interferon signals confirmed a role for this axis in controlling, at least in part, the proliferative reinvigoration of TEXprog cells.
Conclusion: Together, we point-out the temporally limited reinvigoration of TEXprog cells as a determinant of the waning response to PD-1 therapy and highlights type I IFN signals as a therapeutically actionable axis to enhance the durability of PD-1 therapy.
