Immunotherapy to Mitigate the Negative Effects of Alcohol on Cancer Progression

描述(申请人提供)：酗酒是一个世界性的问题。长期酗酒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发病率，还会降低癌症患者的存活率。肿瘤免疫治疗是控制肿瘤进展、延长癌症患者生存时间的最有前景的方法之一。然而，关于长期饮酒如何影响抗肿瘤免疫的认识存在很大差距，这严重阻碍了开发有效的免疫治疗方法来治疗因长期饮酒而导致免疫缺陷的人的癌症。本申请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，从而提高患有黑色素瘤的宿主的存活率，并增强酒精对黑色素瘤的抗转移活性。这一应用的中心假设是，增加和维持CD8+T细胞的数量和功能将减轻酒精/黑色素瘤相互作用造成的负面影响，并导致携带S.C.的宿主存活增加。治疗黑色素瘤和增强与饮酒有关的抗肿瘤作用。为了实现本申请的目标，将追求以下目标：1)确定一种独特的IL-15/IL-15受体复合体与舒尼替尼(一种抑制髓系抑制细胞和T调节细胞的药物)的作用和免疫机制(S)，以抑制长期饮酒的宿主的生长并提高注射了黑色素瘤肿瘤的宿主的存活率。四个子目标将研究这些影响背后的机制(S)。2)确定该疗法对黑色素瘤转移的特异性作用。这项研究将极大地提高对长期饮酒与黑色素瘤进展之间相互作用的免疫机制的了解，并极大地推动使用这种免疫疗法治疗酒精滥用与黑色素瘤患者的进展。这种方法有可能很快被转化为酒精滥用患者、黑色素瘤患者以及潜在的其他类型癌症患者的临床试验，特别是那些免疫缺陷的患者。

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.