Chapter 4 │ Page 118 vivo, after treatment of melanoma tumors with NTP [18]. The in vitro e ects were attributed to the observed change of surface ligand expression on the treated cancer cells. Indeed, NK cell activity relies on the balance between activating and inhibiting signals received through surface receptors, which bind to relevant ligands on the target cell membrane [23]. The interaction between these immune cells and cancer cells is complex, involving numerous ligand-receptor interactions that contribute to the delicate activating/ inhibiting balance. Hence, a comprehensive analysis of several key tumor cell-NK cell axes would enhance our understanding of the signaling mechanisms underlying the improved NK cytotoxicity. Among the key ligands that inhibit NK cells are major histocompatibility complex class 1 (MHC-I) molecules. Unlike antigen-specific T cells, which detect the altered self of cancer cells via intracellular peptides presented by MHC-I, NK cells detect the presence of MHC-I itself. The absence of MHC-I – termed “missing self” – triggers NK cell activation. NK cells express several receptors that recognize MHCI, with killer immunoglobulin-like receptors (KIR) recognizing the classical HLA-A, B and C ligands, and natural killing group 2, type A, (NKG2A) acting as an inhibitory receptor for the non-classical MHC-I complex HLA-E [23-26]. We previously showed altered expression of both HLA-A/B/C and HLA-E on skin cancer cells after NTP treatment in vitro [22]. The fact that NTP treatment is able to change the expression of surface ligands that are important for cancer – immune cell crosstalk is now observed in several studies, and is an appealing therapeutic characteristic for further investigation [18, 22, 27]. In addition to a ecting the expression of ligands on the cancer cell surface, RONS can interact directly with the ligands already expressed on the cells. NTP treatment can induce a broad range of post-translational modifications (PTMs) in proteins [28], which can lead to conformational changes and a ect their ability to bind to
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