Abstract
Human melanoma cells express various tumour antigens that are recognized by CD8+ cytotoxic T lymphocytes (CTLs) and elicit tumour-specific responses in vivo. However, natural and therapeutically enhanced CTL responses in melanoma patients are of limited efficacy. The mechanisms underlying CTL effector phase failure when facing melanomas are still largely elusive. Here we show that, on conjugation with CTL, human melanoma cells undergo an active late endosome/lysosome trafficking, which is intensified at the lytic synapse and is paralleled by cathepsin-mediated perforin degradation and deficient granzyme B penetration. Abortion of SNAP-23-dependent lysosomal trafficking, pH perturbation or impairment of lysosomal proteolytic activity restores susceptibility to CTL attack. Inside the arsenal of melanoma cell strategies to escape immune surveillance, we identify a self-defence mechanism based on exacerbated lysosome secretion and perforin degradation at the lytic synapse. Interfering with this synaptic self-defence mechanism might be useful in potentiating CTL-mediated therapies in melanoma patients.
Highlights
Human melanoma cells express various tumour antigens that are recognized by CD8 þ cytotoxic T lymphocytes (CTLs) and elicit tumour-specific responses in vivo
We have previously shown that human CTL interacting in vitro with antigen-pulsed melanoma cells are efficiently triggered to lytic granule secretion, yet melanoma cells can resist for prolonged time to CTL-mediated cytoxicity[22]
As target cells we employed the metastatic melanoma cell line D10 that we have previously characterized for its sustained resistance to CTL-mediated cytotoxicity[22] and JY cells, an Epstein–Barr virus (EBV)-transformed B-cell line largely employed as a conventional target cell for human CTL23
Summary
Human melanoma cells express various tumour antigens that are recognized by CD8 þ cytotoxic T lymphocytes (CTLs) and elicit tumour-specific responses in vivo. Inside the arsenal of melanoma cell strategies to escape immune surveillance, we identify a self-defence mechanism based on exacerbated lysosome secretion and perforin degradation at the lytic synapse Interfering with this synaptic self-defence mechanism might be useful in potentiating CTL-mediated therapies in melanoma patients. Several strategies are currently being evaluated, including vaccination with dendritic cells carrying tumour antigens, adoptive transfer of tumour-specific CTL and treatment with immune-checkpoint inhibitors[5,6,7,8,9] These strategies are mostly focused on strengthening CTL activation and effector function rather than on weakening tumour cell resistance to CTL attack. Our results show that melanoma cells rapidly respond to CTL at the lytic synapse by a secretory burst of lysosome/late endosomes (LLE) This leads to cathepsin-mediated degradation of perforin. They may inspire new therapeutic approaches complementary to the immuno-modulatory strategies being currently used for the treatment of melanoma patients
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