T cell senescence and CAR-T cell exhaustion in hematological malignancies

Abstract

T cell senescence has been recognized to play an immunosuppressive role in the aging population and cancer patients. Strategies dedicated to preventing or reversing replicative and premature T cell senescence are required to increase the lifespan of human beings and to reduce the morbidity from cancer. In addition, overcoming the T cell terminal differentiation or senescence from lymphoma and leukemia patients is a promising approach to enhance the effectiveness of adoptive cellular immunotherapy (ACT). Chimeric antigen receptor T (CAR-T) cell and T cell receptor-engineered T (TCR-T) cell therapy highly rely on functionally active T cells. However, the mechanisms which drive T cell senescence remain unclear and controversial. In this review, we describe recent progress for restoration of T cell homeostasis from age-related senescence as well as recovery of T cell activation in hematological malignancies.

Keywords: CAR-T cells; Hematological malignancy; Senescence; T cell activation; T cells.

Fig. 1

Schematic model of age and HCMV infection related T cell immunosenescence in the peripheral blood of human. Memory inflation due to latent HCMV infections and thymic involution lead to a shift in T cell distribution from mainly naïve and memory T cells towards effector and senescent T cells with progressing age. Senescent T cells are characterized by shortening of telomeric ends, decrease in telomerase activity, and loss of CD27 and CD28 expression. Markers of T cell senescence include KRLG1, CD57, and the recently identified receptor TIGIT

Fig. 2

Replacement, reprogramming, and restoration strategies for reconstitution of senescent and exhausted cells in T cell pool. (1) Replacement: targeting of directed apoptosis in senescent cells as shown by Baar et al. and rebuilding the T cell pool by ASCT. Top left: blockage of P53/FOXO4 binding in fibroblasts using a bioengineered FOXO4-DRI peptide. Top right: collection, purification, and expansion of hematopoietic stem cells, followed by cryopreservation and reinfusion into patient after chemotherapy. (2) Reprogramming: isolation of senescent and exhausted antigen-specific T cells followed by reprogramming into IPSCs, expansion, induction of T cell lineage, and transduction of engineered CAR and TCR before injection. (3) Restoration: preparation of a functional thymus organoid by thymectomy of cadaveric donor, isolation of TEM, transduction with recipient MHC, and recellularization of bioengineered organoid scaffold before transplantation into recipient

Fig. 3

Mechanism of T cell senescence induction in the tumor microenvironment and strategies for revision of T cell senescence for TCR- and CAR-T cell therapy. Treg and tumor cells use cAMP as a key component in senescence induction of naive and effector T cells. Induction of senescence in T cells leads to a loss of CD27 and CD28 and an amplification of immunosuppression in the tumor microenvironment. Interference with p38 and ERK1/2 as well as activation of TLR8 signaling by poly-G3 and ssRNA40 downregulates cAMP levels in Treg and tumor cells, disrupting induction of senescence and immunosuppression. Functional T cells then can be further used in adoptive immunotherapies. Alternatively, senescent T cells can be reprogrammed for dedifferentiation to use in TCR- and CAR-T cell therapies or targeted for apoptosis to help to recover the homeostasis of T cell subsets in patients with hematological malignancies