Immunotherapy to Mitigate the Negative Effects of Alcohol on Cancer Progression

描述（由申请人提供）：酗酒是一个世界性的问题。长期滥用酒精会导致免疫系统受损，这是增加癌症发病率的一个因素。流行病学证据表明，长期饮酒不仅会增加包括黑色素瘤在内的癌症的发病率，还会降低癌症患者的生存率。肿瘤免疫治疗是控制肿瘤进展和延长癌症患者生存期最有希望的方法之一。然而，关于长期饮酒如何影响抗肿瘤免疫的知识存在很大差距，这严重阻碍了有效免疫治疗方法的发展，以治疗因长期酗酒而存在免疫缺陷的癌症患者。本应用的目的是评估一种新的免疫治疗方法，以恢复和增强抗肿瘤免疫反应，从而提高黑色素瘤宿主的存活率，并增强酒精对黑色素瘤的抗转移活性。本应用的中心假设是，增加和维持CD8+ T数量和功能将减轻酒精/黑色素瘤相互作用引起的负面影响，并导致携带sc黑色素瘤的宿主的存活率增加，并增强与饮酒相关的抗转移作用。为了实现这一应用的目标，将追求以下目标：1)确定一种独特的IL-15/ IL-15受体复合物在有和没有舒尼替尼的情况下的作用和免疫机制，舒尼替尼是一种抑制髓源性抑制细胞和T调节细胞的药物，可以抑制长期饮酒和注射黑色素瘤肿瘤的宿主的生长和增加存活。四个子目标将检验这些效应背后的机制。2)确定该治疗对黑色素瘤转移的具体效果。这项研究将极大地增强对慢性酒精摄入与黑色素瘤进展之间相互作用的免疫机制的理解，并显著推进使用这种免疫疗法治疗酒精滥用黑色素瘤患者的进展。这种方法有可能迅速转化为患有黑色素瘤和其他类型癌症的酗酒患者的人体临床试验，特别是那些有免疫缺陷的患者。

DESCRIPTION (provided by applicant): 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.