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

摘要 虽然在癌症治疗方面已经取得了重大进展，但确定哪些患者仍是一个挑战 将从治疗方案中受益最大，这是个性化医疗的最终目标。解决问题的关键 为特定癌症选择最有效的治疗方法是了解区分的生物学基础 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素治疗的。 化疗和放射治疗，但免疫肿瘤学(IO)药物的新临床成功 成功的基础是生物学上的免疫渗透需要新的策略来模拟最优 组合。由于细胞毒治疗是癌症患者治疗的关键组成部分，哺乳动物模型 这代表了一系列DNA损伤反应缺陷(DDRD)，因此对不同的药物敏感， 会提高翻译研究的水平。同样，癌症逃避抗癌治疗的多种机制 肿瘤免疫需要在转译研究中得到体现。目前大多数临床前缺乏多样性 模型限制了它们作为系统评估肿瘤生物学这些方面的平台的适用性。vt.给出 IO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模型 一种系统，其中定义了肿瘤DDRD和免疫浸润物，以便可以容易地组合 学习。我们建议使用小鼠肿瘤来源的移植(MTDT)来治疗TrP53缺失的乳腺癌 我们产生并表征了异质性，与人类癌症的相关性，以及 证明这些同基因癌的DDR缺陷并评估相应的可重复性 基线免疫细胞渗入。我们将对肿瘤和免疫特征进行多重分析，并 它们与肿瘤对辐射的反应有关，这是一种经典的DNA损伤疗法，可以说是最 广泛使用的细胞毒疗法。这些研究的结果直接回应了FOA，包括 该模型的标准化实施方案、肿瘤类型的综合分析和存储库 样本、数据和活组织。这个项目的成功将提供一种手段来进行机械化 以及使用定义的肿瘤DDRD和免疫浸润物成分进行的转译研究，用于开发患者- IO和细胞毒治疗的特定个性化治疗。

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.