The two faces of IL-6 in the tumor microenvironment

Abstract

Within the tumor microenvironment, IL-6 signaling is generally considered a malevolent player, assuming a dark visage that promotes tumor progression. Chronic IL-6 signaling is linked to tumorigenesis in numerous mouse models as well as in human disease. IL-6 acts intrinsically on tumor cells through numerous downstream mediators to support cancer cell proliferation, survival, and metastatic dissemination. Moreover, IL-6 can act extrinsically on other cells within the complex tumor microenvironment to sustain a pro-tumor milieu by supporting angiogenesis and tumor evasion of immune surveillance. A lesser known role for IL-6 signaling has recently emerged in which it plays a beneficial role, presenting a fairer face that opposes tumor growth by mobilizing anti-tumor T cell immune responses to attain tumor control. Accumulating evidence establishes IL-6 as a key player in the activation, proliferation and survival of lymphocytes during active immune responses. IL-6 signaling can also resculpt the T cell immune response, shifting it from a suppressive to a responsive state that can effectively act against tumors. Finally, IL-6 plays an indispensable role in boosting T cell trafficking to lymph nodes and to tumor sites, where they have the opportunity to become activated and execute their cytotoxic effector functions, respectively. Here, we discuss the dual faces of IL-6 signaling in the tumor microenvironment; the dark face that drives malignancy, and the fairer aspect that promotes anti-tumor adaptive immunity.

Murine allogeneic CD19 CAR T cells harbor potent antileukemic activity but have the potential to mediate lethal GVHD

“…34 By delaying the DLI and allowing full engraftment of BM-derived IL-6 2/2 cells following allo-BMT, we were able to significantly decrease CAR-associated GVHD. Consistent with the complexities of IL-6 production in tumor immunology, 44 our finding that loss of IL-6-producing capacity in BM-derived cells was sufficient to prevent GVHD provides insights into the potential source of IL-6 in the setting of CRS and suggests that, although CAR T cells can produce IL-6, they may not be the primary source. Finally, complete absence of IL-6 from BM, recipient, and CAR T cells did not prevent leukemic control in both syngeneic and allogeneic settings, suggesting that IL-6 may not be essential for CAR T-cell efficacy.…”

Role of liver ICAM-1 in metastasis

“…Aside from the factors secreted by HSCs and LSECs, tumor cells are stimulated by KCs present in the liver sinusoids, which are known to promote tumor progression at multiple levels, including promoting adhesion, proliferation, immune tolerance and angiogenesis (40). Ligand binding to ICAM-1 activates KC secretion of IL-6 (41), which induces cell proliferation via the STAT3 pathway, and stimulates the degradation of surrounding ECM via increased secretion of matrix metalloproteinases (MMPs) (101). IL-6 has been also implicated in the differentiation of human monocytes to M2 macrophages (102), a mechanism that probably also occurs in liver and is related to tumor progression (103).…”

PIAS1 inhibited the metastasis of gastric cancer cell by epithelial-mesenchymal transition regulation within the inflammatory microenvironment

“…IL-6 mediates several important physiological functions, including the control of the acute-phase inflammatory response and the support of cell growth and survival (24). Several studies have suggested that IL-6 is a key mediator of the development of metastatic potential in cancer cells (25,26). Previous studies have indicated that IL-6 promotes the initial steps of cancer metastasis, potentially by upregulating MMP-9 through the PI3K/Akt signal pathway (27,28), and it has been demonstrated that IL-6 induces EMT through the expression of molecular markers (29,30).…”