Resisting T cell attack: tumor-cell-intrinsic defense and reparation mechanisms

Cytotoxic T lymphocytes (CTLs) are equipped with an arsenal of different weapons, from soluble perforin/granzyme to the newly discovered supramolecular attack particles, which are deployed against tumor cells on antigen recognition.Despite the specificity, rapidity, and intensity of CTL attack, tumor cells possess a multitude of constitutive and inducible mechanisms to counteract attacks.Some of these defense mechanisms (e.g., synaptic membrane repair) are ultrarapid and engaged with commensurate rapidity as degranulation, while others (e.g., phosphatidylserine enrichment on the outer membrane) may be engaged constitutively or induced on exposure to other noxious stimuli.Combinatorial therapies that synergize with immunotherapy approaches to inhibit or overwhelm resistance mechanisms are needed to ensure that fully armed and activated CTLs effectively eliminate their targets.