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Tumor-immune profiling of murine syngeneic tumor models as a framework to guide mechanistic studies and predict therapy response in distinct tumor microenvironments

机译：小鼠同源肿瘤模型的肿瘤免疫特征分析作为指导机制研究和预测不同肿瘤微环境中治疗反应的框架

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Mouse syngeneic tumor models are widely used tools to demonstrate activity of novel anti-cancer immunotherapies. Despite their widespread use, a comprehensive view of their tumor-immune compositions and their relevance to human tumors has only begun to emerge. We propose each model possesses a unique tumor-immune infiltrate profile that can be probed with immunotherapies to inform on anti-tumor mechanisms and treatment strategies in human tumors with similar profiles. In support of this endeavor, we characterized the tumor microenvironment of four commonly used models and demonstrate they encompass a range of immunogenicities, from highly immune infiltrated RENCA tumors to poorly infiltrated B16F10 tumors. Tumor cell lines for each model exhibit different intrinsic factors in vitro that likely influence immune infiltration upon subcutaneous implantation. Similarly, solid tumors in vivo for each model are unique, each enriched in distinct features ranging from pathogen response elements to antigen presentation machinery. As RENCA tumors progress in size, all major T cell populations diminish while myeloid-derived suppressor cells become more enriched, possibly driving immune suppression and tumor progression. In CT26 tumors, CD8 T cells paradoxically increase in density yet are restrained as tumor volume increases. Finally, immunotherapy treatment across these different tumor-immune landscapes segregate into responders and non-responders based on features partially dependent on pre-existing immune infiltrates. Overall, these studies provide an important resource to enhance our translation of syngeneic models to human tumors. Future mechanistic studies paired with this resource will help identify responsive patient populations and improve strategies where immunotherapies are predicted to be ineffective.
机译：小鼠同源基因模型被广泛用于证明新型抗癌免疫疗法的活性。尽管它们被广泛使用，但是对它们的肿瘤免疫成分及其与人肿瘤的相关性的全面了解才刚刚开始出现。我们建议每个模型都具有独特的肿瘤免疫浸润特征，可以用免疫疗法进行探测以告知具有相似特征的人类肿瘤的抗肿瘤机制和治疗策略。为了支持这一工作，我们对四种常用模型的肿瘤微环境进行了表征，并证明它们涵盖了多种免疫原性，从高度免疫性浸润的RENCA肿瘤到渗透性较差的B16F10肿瘤。每个模型的肿瘤细胞系在体外均表现出不同的内在因素，这些因素可能会影响皮下植入后的免疫浸润。类似地，每种模型的体内实体瘤都是独特的，每种肿瘤都富含从病原体应答元件到抗原呈递机制的独特特征。随着RENCA肿瘤的发展，所有主要的T细胞群都在减少，而髓样来源的抑制细胞变得更加富集，可能会推动免疫抑制和肿瘤的发展。在CT26肿瘤中，CD8 T细胞密度反常增加，但随着肿瘤体积的增加而受到抑制。最后，基于部分依赖于既有免疫浸润的特征，跨越这些不同的肿瘤免疫区域的免疫疗法治疗分为反应者和非反应者。总体而言，这些研究提供了重要的资源，可增强我们对人类肿瘤的同基因模型的翻译。未来的机械研究与该资源搭配使用将有助于识别反应迅速的患者人群，并改善免疫疗法被认为无效的策略。

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