CTL cytotoxic activity disruption

CTLs or CD8+ T cells are key components of the adaptive immune system, playing a crucial role in protecting against viral infections, bacteria, and tumor development. In the context of cancer, CTLs kill tumor cells after recognizing tumor-derived peptides presented on MHC class I molecules through their T-cell receptor. Upon activation, CTLs form an immunological synapse with the target cell (including cancer cells) and deploy three main killing pathways(Raskov et al., 2021): first, these cells can kill target cells indirectly through the release of cytokine factors like TNFα or IFN-γ (Hoekstra et al., 2024). Second, in the granule exocytosis pathway, CTLs release perforin, which forms pores in the tumor cell membrane, allowing granzymes to enter and trigger caspase-dependent apoptosis. Finally, in the death receptor pathway, CTLs express Fas ligand (FasL) that binds Fas (CD95) on the cell surface of tumor cells, activating their extrinsic apoptotic cascade (Preglej and Ellmeier, 2022).

However, the cancer cells can deactivate and inhibit CTLs, and, as a result, facilitate the tumor immune evasion. In this context, the effectiveness of CTLs is hindered by immunosuppressive mechanisms involving cancer-associated fibroblasts, M2 macrophages, and particularly regulatory T cells (Tregs), which can block the CTLs cytotoxic activity through the TGF-β pathway (Chen et al., 2005). Alternatively, continuous antigenic stimulation also leads to CTLs exhaustion, generating heterogeneous subpopulations, some of which remain responsive to immune checkpoint blockade (Chen et al., 2024).

Anti-cancer therapies targeting PD1/PD-L1 aim to restore CTLs function. Combined approaches, such as inhibiting the ICoS (Inducible Co-Stimulator) pathway before a PD1 therapy, are promising (Geels et al., 2024). Finally, the adoption of genetically engineered CTLs (CAR-T) is an example of advances in enhancing their specificity and tumor-killing efficacy (Brudno et al., 2024).