Definition of Immune Infiltrate Phenotype and DNA Damage Response Deficits Across Diverse Murine Mammary Carcinomas

摘要 虽然癌症治疗取得了重大进展，但挑战仍然是确定哪些患者 将从治疗方案中受益最多，这是个性化医疗的最终目标。的关键 选择对特定癌症最有效的治疗方法是了解不同癌症的生物学基础， 结果和对癌症治疗的内在敏感性。几乎所有的癌症都是用细胞毒性药物治疗的。 化疗和放射治疗，但免疫肿瘤学（IO）药物的临床成功， 成功取决于免疫渗透的生物学特性，这需要新的策略来模拟最佳 组合。由于细胞毒性疗法是癌症患者治疗的关键组成部分，因此哺乳动物模型 这代表了一系列DNA损伤反应缺陷（DDRD），因此对不同试剂的敏感性， 将改善转化研究。同样，癌症逃避抗- 肿瘤免疫需要在转化研究中表现出来。目前大多数临床前研究缺乏多样性 模型限制了它们作为系统评价肿瘤生物学这些方面的平台的适用性。给定 信息作战方法的范围和DDRD的多样性，一个关键的未满足的翻译要求是一个模型 系统，其中肿瘤DDRD和免疫浸润物都被定义，使得可以容易地组合 研究了我们提出使用Trp 53缺失乳腺癌的鼠肿瘤来源的移植物（mTDT）， 我们已经产生并表征了异质性，与人类癌症的相关性， 重复性，以证明这些同源癌的DDR缺陷，并评估相应的 基线免疫细胞浸润。我们将实施肿瘤和免疫特征的多重分析， 将它们与肿瘤对辐射的反应联系起来，辐射是一种典型的DNA损伤疗法， 广泛使用的细胞毒疗法。这些研究的产品直接响应于FOA， 该模型的标准化实施方案，肿瘤类型的综合分析，以及储存库 标本数据和活体组织该项目的成功将提供一种手段， 以及使用确定的肿瘤DDRD和免疫浸润物组合物进行的转化研究， 针对IO和细胞毒性疗法的特异性个性化疗法。

Abstract While major strides have been made in cancer treatment, the challenge remains to determine which patients will benefit most from a therapeutic regimen, which is the ultimate goal of personalized medicine. The key to choosing the most effective therapy for a given cancer is understanding the biological basis for differential outcomes and intrinsic sensitivity to cancer therapies. Almost all cancers are treated with cytotoxic chemotherapy and radiation therapy but the emerging clinical success of immunoncology (IO) drugs whose success is predicated on the biology of the immune infiltrate requires new tactics to model optimal combinations. As cytotoxic therapy is a critical component of cancer patient treatment, mammalian models that represent a range of DNA damage response deficits (DDRD), and hence sensitivity to different agents, would improve translational research. Likewise, the multiple mechanisms by which cancer evades the anti- tumor immunity need to be represented in translational research. Lack of diversity in most current preclinical models limits their applicability as a platform for systemic evaluation of these aspects of tumor biology. Given the range of IO approaches and the diversity of DDRD, a critical unmet translational requirement is a model system in which both the tumor DDRD and the immune infiltrate is defined so that combinations can be readily studied. We propose to use murine tumor derived transplants (mTDT) of Trp53 null mammary carcinomas that we have generated and characterized in regard to heterogeneity, relevance to human cancer, and reproducibility to credential the DDR deficits of these syngeneic carcinomas and to evaluate corresponding baseline immune cell infiltrates. We will implement multiplex analysis of tumor and immune features and correlate them with tumor response to radiation, a canonical DNA damaging therapy and arguably the most widely used cytotoxic therapy. The product of these studies is directly responsive to the FOA consisting of a protocol for standardized implementation of this model, comprehensive analysis of tumor types, and repository of specimens, data, and viable tissue. The success of this project will provide a means to conduct mechanistic and translational studies using defined tumor DDRD and immune infiltrate composition for developing patient- specific personalized therapy to IO and cytotoxic therapies.