Immune Enhancement and Therapy of Cancer

描述（由申请人提供）： 该MMHC联盟提案将解决致癌作用的免疫生物学，特别是与器官特异性癌症发展机制相关的三个关键问题，以及旨在治疗或预防癌症的策略，如几种人类癌症基因工程小鼠模型所揭示的和将要研究的。联盟团队的目标集中在： i）阐明免疫增强的细胞和分子机制，由此募集先天性和获得性免疫系统的细胞以浸润肿瘤性病变，其中它们已经显示能够部分地通过激活血管生成和放大肿瘤细胞生长而功能性地增强肿瘤性进展; ii）鉴定在某些小鼠模型中明显的对T细胞炎症和杀死实体瘤的隐含屏障的分子基础，并进一步评估其一般性，和 iii）改进在器官特异性致癌的完全免疫活性模型中诱导有效T细胞免疫疗法的策略，评估并寻求规避免疫增强和炎症屏障对功效的潜在干扰。 该联盟小组将研究肿瘤免疫生物学的这些相互关联的方面在一组选定的器官特异性癌症，乳腺癌，子宫颈癌和胰岛癌中的调节和表现。该小组将询问免疫增强和炎症屏障是否是这些器官中癌发生的癌前和新生肿瘤阶段的因素，和/或良好建立的实体瘤的持续生长和进展。实验设计将揭示免疫增强和炎症屏障是否随器官部位和进展阶段而变化，并提供对这些参数可能影响肿瘤免疫治疗成功的可能性的见解。通过结合免疫增强或炎症屏障的机制性破坏来提高T细胞免疫对乳腺、宫颈和胰腺癌前病变或恶性病变的疗效的前景将在临床前试验中进行评估。一个由肿瘤生物学家和免疫学家组成的杰出团队已经聚集在一起，以他们共同的能力和互补的专业知识来追求这些战略目标。

DESCRIPTION (provided by applicant): This MMHC consortium proposal will address the immunobiology of carcinogenesis, in particular three critical issues related to mechanisms by which organ specific cancers develop, and to strategies aimed at treating or preventing cancer, as revealed by and to be studied in several genetically engineered mouse models of human cancer. The goals of the consortium team center upon: i) elucidating the cell and molecular mechanisms of immune enhancement, whereby cells of the innate and acquired immune system are recruited to infiltrate neoplastic lesions, wherein they have been shown to be capable of functionally enhancing neoplastic progression, in part by activating angiogenesis and amplifying tumor cell growth; ii) identifying the molecular basis of implicit barriers to T cell inflammation and killing of solid tumors that are evident in certain mouse models and further assessing its generality, and iii) refining strategies for induction of efficacious T cell immunotherapies in fully immunocompetent models of organ-specific carcinogenesis, both assessing and seeking to circumvent the potential interference with efficacy by immune enhancement and inflammatory barriers. The consortium team will investigate the regulation and manifestation of these interrelated facets of tumor immunobiology in a select group of organ-specific cancers, of breast, cervix, and pancreatic islet. The group will ask whether immune enhancement and inflammatory barriers are factors for premalignant and nascent tumor stages of carcinogenesis in these organs, and/or for the continuing growth and progression of well established solid tumors. The experimental designs will reveal whether immune enhancement and inflammatory barriers vary as a function of organ site and stage of progression, and provide insight into the possibility that these parameters can impact upon the success of tumor immunotherapy. The prospects for improving the efficacy of T cell immunity against either premalignant or malignant lesions in breast, cervix, and pancreas by combining mechanism-based disruptions in immune enhancement or inflammatory barriers will be assessed in preclinical trials. A remarkable group of tumor biologists and immunologists has been assembled to pursue these strategic goals with their collectively enabling and complementary expertise.