IFN-γ is essential for the inhibition of B16BL6 melanoma lung metastasis in chronic alcohol drinking mice

Abstract

We previously found that chronic alcohol consumption (20% w/v in drinking water) that models the level consumed by human alcoholics, when administered to female C57BL/6 mice inhibits B16BL6 melanoma metastasis to the lung; however, the mechanism is not known. Chronic alcohol consumption increases IFN-γ producing NK, NKT, CD4+, and CD8+ T cells. To examine the impact of IFN-γ on metastasis, we inoculated B16BL6 melanoma cells i.v. into control and chronic alcohol drinking IFN-γ knockout (KO) mice. Knockout of the ifn-γ gene abrogated the anti-metastatic effects associated with alcohol consumption. We examined metastasis in common gamma-chain (γC) KO mice, which are deficient in NK, NKT and CD8+ T cells, and in Vα14Jα281−/− KO mice, which are deficient in invariant NKT (iNKT) cells, in order to assess the importance of specific IFN-γ producing cell types to this effect. We found that the antimetastatic effect of alcohol was still present in γC KO mice and also in γC KO mice depleted of Gr-1+ cells. Knockout of iNKT cells reduced the degree but not the antimetastatic effect associated with alcohol. These results indicate that the anti-metastatic effect induced by chronic alcohol consumption is IFN-γ dependent and that multiple IFN-γ producing cell types contribute to this effect.

Chronic alcohol consumption inhibits melanoma growth but decreases the survival of mice immunized with tumor cell lysate and boosted with α-galactosylceramide

“…We previously reported that chronic alcohol consumption increases IFN-γ-producing memory T cells, NK cells and NKT cells in the non-melanoma injected mice [25, 28, 29, 34]. The percentage of IFN-γ-producing T cells in the alcohol-consuming mice continues to be elevated up to 11 days after s.c. melanoma inoculation as compared to water-drinking mice [26].…”

“…We found that chronic alcohol consumption along with advancing growth of s.c. melanoma leads to inhibition in the expansion of memory and melanoma-specific CD8 + T cells, acceleration in the decay of Th1 cytokine producing CD8 + T cells [26], and compromised circulation of mature B cells [27]. Chronic alcohol consumption also increases invariant NKT (iNKT) cells and especially IFN-γ-producing iNKT cells [28] [29]. iNKT cells are specific T cells that recognize lipid antigens and produce a broad spectrum of cytokines upon activation [30].…”

Alcohol Consumption and Antitumor Immunity: Dynamic Changes from Activation to Accelerated Deterioration of the Immune System

“…The inhibition of B16BL6 melanoma lung metastasis in mice chronically consuming alcohol was abrogated in IFN-γ knockout (KO) mice ( Fig. 18.1 ) [ 43 ]. This suggests that the anti-metastatic effect induced by chronic alcohol consumption is dependent on the IFN-γ signaling pathway and that multiple cell types are involved in this process.…”

“…The anti-metastatic effect induced during alcohol consumption is maintained in γC knockout mice, which lack NK, B, and CD8 + T cells ( Fig. 18.1 ) [ 43 ]. While tumor metastasis is a complicated process, IFN-γ plays an important role in control of melanoma metastasis [ 44 ].…”

A Preclinical Model of Chronic Alcohol Consumption Reveals Increased Metastatic Seeding of Colon Cancer Cells in the Liver

“…Several epidemiologic studies presented controversial effects of alcohol consumption on cancer-associated outcomes, including survival rate and metastasis (5). An animal study showed chronic alcohol consumption accelerated melanoma metastasis into the lung by suppression of natural killer (NK) cells (6), whereas another study presented suppression of melanoma by alcohol intake via activating IFNg-producing immune cells (7).…”