Intratumoral checkpoint subversion as a strategy for minimizing adverse effects: Harvesting the power of TILs without harvesting TILs

摘要

One of the most significant clinicaladvances in cancer immunotherapy todate has been the targeting of the immune“checkpoints” that inhibit effector T-cellfunction. Cytotoxic T lymphocyte-associatedprotein 4 (CTLA4), which was oneamong the first checkpoint regulators tobe characterized, is transiently expressedby activated effector T cells and constitutivelyexpressed on regulatory T cells(Tregs).1 CTLA4 inhibits T cells by atleast 2 mechanisms: (1) by preferentiallybinding CD80 or CD86 on antigen-presentingcells (APCs), thereby antagonizingthe co-stimulatory signals delivered toT cells via CD28;2 and (2) by sending ananergy-inducing signal via the intracellularkinases phosphoinositide-3-kinase (PI3K)and AKT1 (also known as protein kinaseB, PKB).3