Studying Immunotherapy Resistance in a Melanoma Autologous Humanized Mouse Xenograft.
Studying Immunotherapy Resistance in a Melanoma Autologous Humanized Mouse Xenograft.
复制标题
研究黑色素瘤自体人源化小鼠异种移植物的免疫治疗耐药性。
DOI：
10.1158/1541-7786.mcr-20-0686
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发表时间：
2021-03
期刊：
影响因子：
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通讯作者：
Jimeno A
中科院分区：
文献类型：
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作者：
Morton JJ;Alzofon N;Keysar SB;Chimed TS;Reisinger J;Perrenoud L;Le PN;Nieto C;Gomez K;Miller B;Yeager R;Gao D;Tan AC;Somerset H;Medina T;Wang XJ;Wang JH;Robinson W;Roop DR;Gonzalez R;Jimeno A
对免疫疗法的抵抗是一个重大挑战，而人体模型的稀缺阻碍了对潜在机制的识别。为了解决这一局限性，我们构建了一个自体人源化小鼠(AHM)模型，该模型使用了造血干细胞和祖细胞(HSPC)以及两名正在接受免疫治疗的黑色素瘤患者的肿瘤。不同于从脐带血来源的HSPC和来自不同捐赠者的肿瘤产生的不匹配的人源化小鼠(MHM)模型，AHM重述了患者特定的肿瘤微环境(TME)。当患者肿瘤植入AHM、MHM和NOD/SCID/IL2RG−/−(NSG)队列时，NSG和MHM队列中肿瘤出现得更早、生长更快。我们观察到，在AHM中分化的免疫细胞相对更有能力进行外周循环，侵袭肿瘤并与TME相互作用。与非人类白细胞抗原(HLA-A)匹配的异源MHM相比，异源的人类白细胞抗原(HLA-A)匹配的队列也产生了较慢的肿瘤生长速度，这表明较不允许的免疫环境抑制了肿瘤的进展。当AHM、MHM和NSG队列接受与原始患者相同的免疫治疗时，AHM中的肿瘤生长加速，与在患者中观察到的进展相似。这种快速增长与免疫细胞渗透减少、干扰素γ相关基因表达减少以及STAT3磷酸化减少有关，这些事件在体外使用肿瘤来源的细胞系复制。移植的成人HSPC可以产生更多的肿瘤浸润性免疫细胞，增加的HLA配型导致肿瘤的启动和生长缓慢，而在进展之后继续免疫治疗可能会矛盾地导致肿瘤的生长增加。
Resistance to immunotherapy is a significant challenge, and the scarcity of human models hinders the identification of the underlying mechanisms. To address this limitation, we constructed an autologous humanized mouse (aHM) model with hematopoietic stem and progenitor cells (HSPCs) and tumors from two melanoma patients progressing to immunotherapy. Unlike mismatched humanized mouse (mHM) models, generated from cord blood-derived HSPCs and tumors from different donors, the aHM recapitulates a patient-specific tumor microenvironment (TME). When patient tumors were implanted on aHM, mHM and NOD/SCID/IL2rg−/− (NSG) cohorts, tumors appeared earlier and grew faster on NSG and mHM cohorts. We observed that immune cells differentiating in the aHM were relatively more capable of circulating peripherally, invading into tumors and interacting with the TME. A heterologous, human leukocyte antigen (HLA-A) matched cohort also yielded slower growing tumors than non-HLA-matched mHM, indicating that a less permissive immune environment inhibits tumor progression. When the aHM, mHM, and NSG cohorts were treated with immunotherapies mirroring what the originating patients received, tumor growth in the aHM accelerated, similar to the progression observed in the patients. This rapid growth was associated with decreased immune cell infiltration, reduced interferon gamma (IFNγ)-related gene expression, and a reduction in STAT3 phosphorylation, events that were replicated in vitro using tumor-derived cell lines. Engrafted adult HSPCs give rise to more tumor infiltrative immune cells, increased HLA matching leads to slower tumor initiation and growth, and continuing immunotherapy past progression can paradoxically lead to increased growth.