Chapter 5 │ Page 180 Cx43 proteins and subsequent functional Cx43-GJs in the cytotoxic IS between CTLs (or NK cells) and cancer cells are required for induction of granzyme Bmediated cell death in these target cells (Figure 1d, see figure caption for more details) [134]. Further investigation into the underlying mechanisms revealed that Cx43 protein accumulation at di erent IS is antigen specific, time dependent, and requires an intact actin cytoskeleton. This process precedes a polarized Ca2+ influx, causing the granzyme B activity in the target cell via the NK cell/target cell lytic IS, while this mechanism is yet to be unraveled in the Cytotoxic T lymphocyte (CTL)- target cell synapse [130,135]. These data enlighten a previously underestimated role of GJs in alternative pathways for immune regulation and activation, and prompt these intercellular structures as potential targets for immunomodulating anti-cancer therapies. Illustrative of this potential is the recent finding that undi erentiated monocytes were able to elicit competent therapeutic CTL responses, solely when Cx43-GJs were established between tumor antigen-loaded monocytes and endogenous DCs in multiple in vivo mouse models [136]. In addition, a novel immunotherapeutic approach, based on immunogenic peptide release in the tumor microenvironment, pointed out that Cx43 protein overexpression and Cx43-GJs opening via posttranslational modifications on target cells are required for the release of tumorderived peptides and adequate anti-tumor responses in several model systems [137]. This research sheds light on the fact that besides mediating direct cell-cell contact, GJs have also a rather unexplored contribution in immunological processes. In addition, a role of other members of the Cx protein family cannot be ruled out, as research into this area is still very limited. 7. OXIDATIVE STRESS ON GJs AS A CANCER THERAPEUTIC STRATEGY One of the major roles of GJs, is the exchange of ions and small molecules between the cytoplasm of adjacently connected cells [51,56]. In this way, GJs may
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