Mind the Gaps in Tumor Immunity: Impact of Connexin-Mediated Intercellular Connections

Abstract

Gap junctions (GJs)-mediated intercellular communications (GJICs) are connexin (Cx)-formed plasma membrane channels that allow for the passage of small molecules between adjacent cells, and are involved in several physiopathological processes, including immune responses against cancer. In general, tumor cells are poorly coupled through GJs, mainly due to low Cx expression or reduced channel activity, suggesting that Cxs may have tumor suppressor roles. However, more recent data indicate that Cxs and/or GJICs may also in some cases promote tumor progression. This dual role of Cx channels in tumor outcome may be due, at least partially, to the fact that GJs not only interconnect cells from the same type, such as cancer cells, but also promote the intercellular communication of tumor cells with different types of cells from their microenvironment, and such diverse intercellular interactions have distinctive impact on tumor development. For example, whereas GJ-mediated interactions among tumor cells and microglia have been implicated in promotion of tumor growth, tumor cells delivery to dendritic cells of antigenic peptides through GJs have been associated with enhanced immune-mediated tumor elimination. In this review, we provide an updated overview on the role of GJICs in tumor immunity, focusing on the pro-tumor and antitumor effect of GJs occurring among tumor and immune cells. Accumulated data suggest that GJICs may act as tumor suppressors or enhancers depending on whether tumor cells interact predominantly with antitumor immune cells or with stromal cells. The complex modulation of immune-tumor cell GJICs should be taken into consideration in order to potentiate current cancer immunotherapies.

Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis

“…In non-tumor tissues Cx31 expression has been identified in keratinocytes, the small intestine, and the colon (45,46). Although roles for various connexins as oncogenes and/or tumor suppressors have been described (39,40), the function of Cx31 in tumorigenesis has not been established.…”

Hypoxic Melanoma Cells Deliver microRNAs to Dendritic Cells and Cytotoxic T Lymphocytes through Connexin-43 Channels

“…In this line, since more than five decades ago, it is known that cancer cells isolate themselves from their cellular environment down-regulating GJIC [ 49 ]. Indeed, aberrant Cx43 expression and its mislocalization, which leads to reduced GJIC, are frequent in different tumors, including melanoma, and predict cancer patient outcome [ 19 , 50 ]. Numerous evidences have shown that Cx43 suppresses tumors via different heterotypic (cancer cell-immune cell or cancer cell-stromal cell) GJICs, as we previously reviewed [ 19 , 23 ].…”

“…Indeed, aberrant Cx43 expression and its mislocalization, which leads to reduced GJIC, are frequent in different tumors, including melanoma, and predict cancer patient outcome [ 19 , 50 ]. Numerous evidences have shown that Cx43 suppresses tumors via different heterotypic (cancer cell-immune cell or cancer cell-stromal cell) GJICs, as we previously reviewed [ 19 , 23 ]. Indeed, Cx43-CJICs have been implicated in different antitumor roles that affect the cancer-immunity cycle ( Figure S4 ).…”

“…Indeed, recent data suggests that miRNAs could be transferred between contacting cells via gap junctions (GJs), and it has been proposed as a novel pathway for intercellular regulation of gene expression [ 17 , 18 ]. GJs are connexin (Cx)-formed channels that through the cell-to-cell shuttling of small molecules regulate a plethora of physiological functions, including immunity [ 19 ]. Connexin-43 (Cx43), the main GJ protein expressed in immune cells [ 19 ], has been shown by us and other groups, to accumulate at immunological synapses, allowing GJ-mediated intercellular communications (GJIC) between lymphocytes and DCs [ 20 , 21 , 22 , 23 ], between cytotoxic cells (CTLs and NK cells) and tumor cells [ 22 , 23 , 24 , 25 ], and between DCs and tumor cells [ 26 ].…”

Mast Cells Interact with Endothelial Cells to Accelerate In Vitro Angiogenesis

“…Gap junctions are intercellular channels that directly connect the cytoplasm of adjacent cells, allowing the passage of current and small signaling molecules[11,49]. A gap junction is composed of two connexons integrated into the plasma membranes of the connected cells forming a channel[50,51]. Each connexon is composed of 6 connexins.…”