Existing patient-derived-xenograft (PDX) mouse models of solid tumors lack a fully tumor-donor matched 'syngeneic' and functional immune system. We developed such a model by engrafting lymphopenic recipient mice with a fresh undisrupted piece of solid tumor, whereby tumor-infiltrating lymphocytes (TIL) expanded in the recipient mice for several weeks. Tumors engrafted in about seventy to eighty percent of syngeneic-immune-system-PDX (SIS-PDX) mice, which harbored tumor-exhausted immune-effector and functional immune-regulatory cells persisting for at least six-months post-engraftment. Interleukin-15 (IL-15)-stimulation in addition to immune checkpoint inhibition (ICI), prevented resistance, resulting in complete or partial response to combined treatment. Further, the depletion of Cytotoxic T lymphocytes (CTLs) and/or Natural Killer (NK) cells from combined immunotherapy in SIS-PDX mice revealed that both cell types are required for the maximal response to tumor. Our novel SIS-PDX model provides a valuable resource for powerful mechanistic and therapeutic studies designed to eradicate solid tumors.

中文翻译：

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在新的患者源性异种移植模型中，需要NK细胞和CTL清除实体瘤

现有的实体瘤患者源性异种移植（PDX）小鼠模型缺乏与肿瘤供体完全匹配的“同基因”和功能性免疫系统。我们通过向淋巴细胞减少的受体小鼠移植新鲜的未破坏的实体瘤，从而使肿瘤浸润淋巴细胞（TIL）在受体小鼠中扩展了几周，从而开发了这种模型。大约70％至80％的同基因免疫系统PDX（SIS-PDX）小鼠植入了肿瘤，这些小鼠具有肿瘤耗尽的免疫效应子，而功能性免疫调节细胞则在移植后至少持续六个月。除免疫检查点抑制（ICI）之外，白介素15（IL-15）的刺激还可以防止耐药性，从而导致对联合治疗的完全或部分反应。进一步，SIS-PDX小鼠中联合免疫疗法对细胞毒性T淋巴细胞（CTL）和/或自然杀伤（NK）细胞的消耗表明，这两种细胞类型都是对肿瘤最大反应所必需的。我们新颖的SIS-PDX模型为根除实体瘤的强大机械和治疗研究提供了宝贵的资源。