Greek Fire, Poison Arrows, and Scorpion Bombs: How Tumor Cells Defend Against the Siege Weapons of Cytotoxic T Lymphocytes

Abstract

CD8+ cytotoxic T lymphocytes (CTLs) are the main cellular effectors of the adaptive immune response against cancer cells, which in turn have evolved sophisticated cellular defense mechanisms to withstand CTL attack. Herein we provide a critical review of the pertinent literature on early and late attack/defense events taking place at the CTL/target cell lytic synapse. We examine the earliest steps of CTL-mediated cytotoxicity (“the poison arrows”) elicited within seconds of CTL/target cell encounter, which face commensurately rapid synaptic repair mechanisms on the tumor cell side, providing the first formidable barrier to CTL attack. We examine how breach of this first defensive barrier unleashes the inextinguishable “Greek fire” in the form of granzymes whose broad cytotoxic potential is linked to activation of cell death executioners, injury of vital organelles, and destruction of intracellular homeostasis. Herein tumor cells deploy slower but no less sophisticated defensive mechanisms in the form of enhanced autophagy, increased reparative capacity, and dysregulation of cell death pathways. We discuss how the newly discovered supra-molecular attack particles (SMAPs, the “scorpion bombs”), seek to overcome the robust defensive mechanisms that confer tumor cell resistance. Finally, we discuss the implications of the aforementioned attack/defense mechanisms on the induction of regulated cell death (RCD), and how different contemporary RCD modalities (including apoptosis, pyroptosis, and ferroptosis) may have profound implications for immunotherapy. Thus, we propose that understanding and targeting multiple steps of the attack/defense process will be instrumental to enhance the efficacy of CTL anti-tumor activity and meet the outstanding challenges in clinical immunotherapy.

T cell-mediated additive cytotoxicity – death by multiple bullets

“…As an emerging theme, CTLs induce intracellular damages, which accumulate over time until a detrimental, non-repairable state is reached [43]. The relative importance of each damage type and corresponding repair mechanism for inducing target cell death remains to be established.…”

Counteracting Immunosuppression in the Tumor Microenvironment by Oncolytic Newcastle Disease Virus and Cellular Immunotherapy

“…CTLs eliminate tumor cells via a combination of killing modes [ 41 ]. Lethal hits at the lytic synapse between a CTL and a tumor cell lead within seconds to sustained Ca 2+ release, damaged membrane and caspase 3 activity.…”

“…Lethal hits at the lytic synapse between a CTL and a tumor cell lead within seconds to sustained Ca 2+ release, damaged membrane and caspase 3 activity. Against this activity tumor cells can induce ultra-rapid defense mechanisms based on the synaptic lysosomal/late endosomal (LLE) membrane repair pathway [ 41 ]. To date, four modalities have been implicated in target cell death upon CTL attack: intrinsic apoptosis, extrinsic apoptosis, pyroptosis and ferroptosis.…”

“…To date, four modalities have been implicated in target cell death upon CTL attack: intrinsic apoptosis, extrinsic apoptosis, pyroptosis and ferroptosis. In addition to the ultra-rapid defense mechanisms, tumor cells are able to establish slower defense mechanisms (e.g., removing damaged organelles) and constitutive defense mechanisms (e.g., upregulation of inhibitors of apoptosis proteins) [ 41 ].…”

Clathrin controls bidirectional communication between T cells and antigen presenting cells

“…[18] In cytotoxic effector T cells, elevation of cytoplasmic Ca 2+ is also required for granule exocytosis leading to target cell killing which can be induced within a few seconds of activation. [19][20][21] Another important signaling event taking place during T cell activation is the covalent attachment of the 8 kDa protein ubiquitin to lysine residues residing in the CD3ζ and δ chains through the process of ubiquitination. [22] Because ubiquitin monomers can attach to each other to form complex polyubiquitin chains and because each monomer can undergo additional modifications, there is a vast number of ways receptors can be modified with this system.…”