OBJECTIVES Investigation of variable response rates to cancer immunotherapies has exposed the immunosuppressive tumor microenvironment (TME) as a limiting factor of therapeutic efficacy. A determinant of TME composition is the tumor location, and clinical data have revealed associations between certain metastatic sites and reduced responses. Preclinical models to study tissue-specific TMEs have eliminated genetic heterogeneity, but have investigated models with limited clinical relevance. METHODS We investigated the TMEs of tumors at clinically relevant sites of metastasis (liver and lungs) and their impact on αPD-1/αCTLA4 and trimAb (αDR5, α4-1BB, αCD40) therapy responses in the 67NR mouse breast cancer and Renca mouse kidney cancer models. RESULTS Tumors grown in the lungs were resistant to both therapies whereas the same tumor lines growing in the mammary fat pad (MFP), liver or subcutaneously could be completely eradicated, despite greater tumor burden. Assessment of tumor cells and drug delivery in 67NR lung or MFP tumors revealed no differences and prompted investigation into the immune TME. Lung tumors had a more immunosuppressive TME with increased myeloid-derived suppressor cell infiltration, decreased T cell infiltration and activation, and decreased NK cell activation. Depletion of various immune cell subsets indicated an equivalent role for NK cells and CD8+ T cells in lung tumour control. Thus, targeting T cells with αPD-1/αCTLA4 or trimAb was not sufficient to elicit a robust antitumor response in lung tumors. CONCLUSION Taken together, these data demonstrate that tissue-specific TMEs influence immunotherapy responses and highlight the importance in defining tissue-specific response patterns in patients.

中文翻译：

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组织特异性肿瘤微环境影响对免疫疗法的反应。

目标 对癌症免疫疗法的不同反应率的研究表明，免疫抑制性肿瘤微环境 (TME) 是治疗效果的限制因素。TME 组成的一个决定因素是肿瘤位置，临床数据揭示了某些转移部位与降低反应之间的关联。研究组织特异性 TME 的临床前模型已经消除了遗传异质性，但研究的模型临床相关性有限。方法 我们在 67NR 小鼠乳腺癌和 Renca 小鼠肾脏中研究了临床相关转移部位（肝和肺）的肿瘤 TME 及其对 αPD-1/α​​CTLA4 和 triAb（αDR5、α4-1BB、αCD40）治疗反应的影响癌症模型。结果 生长在肺部的肿瘤对这两种疗法都有抗药性，而在乳腺脂肪垫 (MFP)、肝脏或皮下生长的相同肿瘤系可以完全根除，尽管肿瘤负荷更大。对 67NR 肺或 MFP 肿瘤中肿瘤细胞和药物递送的评估显示没有差异，并促使对免疫 TME 进行调查。肺肿瘤具有更强的免疫抑制性 TME，骨髓来源的抑制细胞浸润增加，T 细胞浸润和活化减少，NK 细胞活化减少。各种免疫细胞亚群的消耗表明 NK 细胞和 CD8+ T 细胞在肺肿瘤控制中具有同等作用。因此，用 αPD-1/α​​CTLA4 或 triAb 靶向 T 细胞不足以在肺肿瘤中引发强烈的抗肿瘤反应。结论 综上所述，