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