Chapter 5 │ Page 179 which Cxs and GJs can act as anti- or pro-tumorigenic agents; and treatmentintrinsic di iculties like target selectivity and competitive inhibition are important issues to solve in order to fully optimize and implement them as cancer treatment. 6. Cxs AND GJs IN IMMUNE ACTIVATION AND IMMUNOTHERAPY Engagement of the patient’s own immunity to recognize and eradicate malignant cells is a very promising anti-tumor strategy, which is highlighted by the prominent role of immunotherapy in the clinical management of cancer and development of new combination strategies. The formation of a stable immunological synapse (IS) enabling intercellular communication is one of the fundamental steps in the immune cell priming and activation process. This includes direct crosstalk between antigen presenting cells (APCs), and T cells and natural killer (NK) cells, or between target (e.g. malignant) cells with cytotoxic T lymphocytes (CTLs) and NK cells (Figure 1b, d; see caption for more details) [129]. Several studies described a role of GJs in the antigenic peptide transfer and crosspresentation mechanism between target cells and APCs, whereby GJs are able to facilitate e ective cell coupling and transport of antigenic peptides with lengths up to 16 amino acids when in extended formation (Figure 1b, see figure caption for more details) [44,45]. Furthermore, functional GJs between DCs and cancer cells were reported in an ex vivo human melanoma model wherein antigen transfer between DCs led to activation and maturation of naive DCs, and subsequently specific CTLs engagement [10]. It was also found that GJs are required for DCs transfer secondary messengers to NK cells for subsequent NK cell activation, although the nature of these molecules is yet to unravel [130]. Mendoza-Naranjo et al. and others identified Cx43 proteins as the key Cx type mediating bidirectional GJs between DCs-DCs and DCs-T cells at the stimulatory IS, leading to antigendependent T cell activation, in both murine and human models (Figure 1b, see figure caption for more details) [131-133]. It was found that e icient polarization of
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