Background The development of immunotherapies holds great promise for the treatment of refractory infections and cancer. Current approaches, although effective in many settings, have limitations that prevent their widespread use. Hence, several aspects require improvements, including the re-wiring of T-cell fates and function. T-cell dysfunction is central to the persistence of several chronic viral infections and the progression of malignancies. Upon activation, T cells can follow several paths of differentiation, leading to terminal effector differentiation and/or exhaustion which are widely recognized as dysfunctional features limiting human immune competence. Furthermore, dysfunctional features induced during laboratory-based manipulations of T-cell products prior to adoptive cell transfer has a determining effect on outcomes. Similarly, repeated antigen encounters after transfer in vivo favors the development of T-cell dysfunction. However, the nature and underlying mechanisms of T-cell dysfunction are still incompletely understood.
Methods Combining genomics, phenotypic and functional analyses in various physiologically and clinically relevant settings, we investigated the key factors leading to T-cell dysfunction. Specifically, we evaluated the impact of repeated stimulations using CD3/CD28-coated beads or antigen-loaded dendritic cells in human T-cell long term cultures, and BCMA-expressing cells for anti-BCMA CAR T cells. We also examined mouse antigen-specific T cells during chronic lymphocytic choriomeningitis virus (LCMV) infection as well as datasets obtained from circulating T cells from acute myeloid leukemia (AML) patients.
Results We identified telomere-independent cellular senescence as a central aspect of exhausted PD-1-expressing T cells following repeated stimulations. Mechanistically, it is associated the induction of p16INK4a. Additionally, we found that cellular senescence features are partly regulated by the activation of caspase-8, through a non-apoptotic function of this molecule not previously described in T cells.
Conclusions We thus conclude that caspase-8 may regulate the balance between apoptosis and proliferation by protecting T cells from cellular senescence. Senescence-associated mechanisms may be seen as key players in T-cell dysfunction occurring following repeated stimulations and as such should be considered as novel immune checkpoints impeding the success of T-cell adoptive immunotherapy in humans.
Ethics Approval This study was approved by the local Maisonneuve-Rosemont Hospital research ethics authorities and participants’ informed consent was obtained (CÉR2020-2141 and CÉR13030).
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