Alcohol abuse is a worldwide problem. Chronic abuse of alcohol leads to a compromised immune system, which is one factor that can increase the incidence of cancer. This is supported by epidemiological evidence indicating that chronic alcohol consumption not only increases the incidence of cancer, including melanoma, but also decreases the survival of cancer patients. Cancer immunotherapy is one of the most promising methods to control tumor progression and extend survival of cancer patients. However, there is a large gap in knowledge as to how chronic alcohol consumption affects antitumor immunity, and this severely hampers the development of effective immunotherapeutic approaches to treat cancer in people who have immune deficits due to chronic alcohol abuse. The objective of this application is to evaluate a novel immunotherapeutic approach to restore and augment antitumor immune responses that lead to increased survival of hosts with melanoma and enhance alcohol's antimetastatic activity against melanoma. The central hypothesis of this application is that augmenting and sustaining CD8+ T numbers and functions will mitigate the negative effects caused by the alcohol/melanoma interaction and result in increased survival of hosts bearing s.c. melanoma and in enhancement of the antimetastatic effect associated with alcohol consumption. To accomplish the objectives of this application the following aims will be pursued: 1) Determine the effect and immune mechanism(s) of a unique IL-15/IL15 receptor complex with and without sunitinib, a drug that inhibits myeloid derived suppressor cells and T regulatory cells, to inhibit growth and increase survival of hosts that drink alcohol chronically ad that are injected with melanoma tumors. Four sub-aims will examine the mechanism(s) underlying these effects. 2) Determine the specific effects of this treatment on melanoma metastasis. This research will greatly enhance understanding of the immune mechanisms involved in the interplay between chronic alcohol consumption and melanoma progression, and significantly advance progress toward using this immunotherapy to treat alcohol abusing patients with melanoma. This approach has the potential of being quickly translated into human clinical trials for alcohol abusing patients with melanoma and potentially other types of cancer and especially for those patients with immune deficits.
An estimated 17.6 million people abuse alcohol or are alcohol-dependent. Alcohol consumption increases cancer incidence and death. This application investigates a novel immune-based therapy to mitigate the negative effects that chronic alcohol consumption has on cancer progression and host survival.
|Zhang, Faya; Little, Alex; Zhang, Hui (2017) Chronic alcohol consumption inhibits peripheral NK cell development and maturation by decreasing the availability of IL-15. J Leukoc Biol 101:1015-1027|
|Meadows, Gary G; Zhang, Hui (2015) Effects of Alcohol on Tumor Growth, Metastasis, Immune Response, and Host Survival. Alcohol Res 37:311-22|
|Zhang, Faya; Zhu, Zhaohui; Meadows, Gary G et al. (2015) Chronic alcohol consumption inhibits melanoma growth but decreases the survival of mice immunized with tumor cell lysate and boosted with ?-galactosylceramide. Int Immunopharmacol 28:359-68|