The anti-tumor immune response involves a series of complex steps mediated by various immune cells and signaling molecules. Cytotoxic T cells (CTLs), also known as “killer” T cells, play a central role by eliminating foreign cells, including cancer cells. Antigen-presenting cells (APCs) facilitate this process by displaying antigen fragments on major histocompatibility complex (MHC) proteins to T cells. Activation of the anti-tumor immune response occurs when a T cell receptor (TCR) binds to an MHC molecule presenting a cancer-derived antigen.
Cancer cells have developed multiple strategies to evade immune detection and disrupt anti-tumor responses. A recent study published in Cell has identified a previously unrecognized mechanism by which melanoma cells inhibit the cytotoxic activity of CTLs.
The study investigates melanosomes, extracellular vesicles secreted by melanoma cells that contribute to a suppressive tumor microenvironment and promote metastasis. The researchers discovered that these melanoma-derived melanosomes also carry MHC molecules.
Melanosomes carrying MHC molecules interact with TCRs on adjacent T cells, leading to T cell dysfunction and preventing their engagement with antigen-loaded MHC molecules necessary for anti-tumor immune activation.
Gilad Levy, a member of the research team, stated, “We discovered that the cancer essentially fires these vesicles at the immune cells that attack it, disrupting their activity and even killing them.”
The study demonstrates that antigens presented by MHC molecules on melanosomes outcompete those presented by APCs, thereby inhibiting immune activation. Additionally, analysis of melanoma patient biopsies revealed that melanosomes sequester T cells and impair their cytotoxic function, effectively preventing them from eliminating cancer cells.
The authors conclude that secretion of MHC-containing vesicles by melanoma cells protects them from CTL-mediated destruction. This study identifies a previously unrecognized immune evasion mechanism in melanoma. The findings indicate that therapeutic strategies targeting melanosome secretion may offer significant benefits for melanoma treatment. Melanoma remains the fifth-most commonly diagnosed cancer in both men and women in the United States presenting a large population of patients who could potentially benefit from new interventions.
Sources: Cell, Immuno Biol, Nat Rev Mol Cell Biol, EMBO J, Jerusalem Post, CA Cancer J Clin