PO.CL05.04 · 临床研究
剖析Adam17内宿主遗传变异所致肿瘤免疫检查点阻断耐药的机制
Dissecting mechanisms of tumor immune checkpoint blockade resistance due to host genetic variation within Adam17
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
anti-PD-1或anti-PDL-1抗体的临床应用（也称为免疫检查点阻断(ICB)治疗）已显示出作为抗癌治疗的潜力。然而，目前仅有10%至30%的癌症患者对ICB产生应答。成功的ICB治疗取决于多种因素，包括肿瘤突变负荷、癌症亚型和患者的种系遗传学。因此，明确宿主遗传学如何影响ICB临床成功率以改善患者结局存在明确需求。我们实验室主要专注于研究多种疾病背景下的转化生长因子-β(TGF-β)信号传导。我们构建了两个配对的同类系NIH/Ola小鼠品系，它们在小鼠12号染色体近端的Tgfbm3b位点分别携带NIH/Ola或C57Bl/6J。已知Tgfbm3b可调节TGFβ信号传导，并涵盖肿瘤坏死因子-α转换酶(TACE，也称为ADAM17)的遗传变异。利用这些植入同基因癌细胞的同类系小鼠，我们生成了初步数据，提示Adam17的C57"低活性"等位基因（在D113N、I613V处存在氨基酸变异）与更好的ICB应答相关，而携带活性NIH等位基因的同类系小鼠则对ICB治疗耐药。鉴于遗传低活性Adam17可增强ICB应答，我们采用了一种高度特异性的TACE小分子抑制剂(TMI-2)，发现它可在两种体内同基因鳞状细胞癌(SCC)模型中使ICB耐药肿瘤对免疫治疗敏感，提示ADAM17活性可能抑制ICB疗效。我们利用流式细胞术和RNA测序技术详细描述了ICB敏感和耐药小鼠模型中（有和无ICB时）的免疫细胞浸润，发现肿瘤微环境中髓系和T细胞浸润存在差异，提示ADAM17可能调控肿瘤微环境格局。我们还有体外数据提示ADAM17的低活性变体可能减少特定免疫细胞类型中免疫细胞对肿瘤坏死因子α(TNFα)的分泌以及TNFα诱导的细胞死亡。TMI-2在人体中是安全的，本研究为将ADAM17作为治疗靶点用于携带ICB耐药癌症的患者提供了支持。本研究还为ADAM17活性在肿瘤生物学中的细胞类型特异性后果提供了宝贵见解，并强调在应用ICB治疗时需考虑患者遗传学。
查看英文原文 English abstract
Clinical application of anti-PD-1 or anti-PDL-1 antibodies, also known as immune checkpoint blockade (ICB) therapy, has shown potential as an anti-cancer treatment. However, currently only 10 to 30 percent of cancer patients respond to ICB. Successful ICB treatment depends on a variety of factors including tumor mutation burden, cancer subtype, and patient germline genetics. Therefore, there is a clear need to understand how host genetics influences ICB clinical success to improve patient outcomes. Our laboratory primarily focuses on the study of transforming growth factor-beta (TGF-beta) signaling across a variety of disease contexts. We have generated two paired congenic NIH/Ola mouse strains that harbor either NIH/Ola or C57Bl/6J across the Tgfbm3b locus on proximal chromosome mouse 12. Tgfbm3b is known to modulate TGFbeta signaling and encompasses genetic variants of tumor necrosis-alpha converting enzyme (TACE, also known as ADAM17). Utilizing these congenic mice implanted with syngeneic cancer cells, we generated preliminary data suggesting that the C57 “hypoactive” allele of Adam17 , with amino acid variation at D113N, I613V, correlates with better response to ICB compared to congenic mice that harbor the active NIH allele, which are resistant to ICB treatment. Considering that inheritance of hypoactive Adam17 enhances ICB response, we employed a highly specific small molecule inhibitor of TACE (TMI-2) finding that it sensitizes ICB-resistant tumors to immunotherapy across two in vivo syngeneic squamous cell carcinoma (SCC) models, suggesting that ADAM17 activity may suppress ICB efficacy. We have detailed the immune cell infiltrate on ICB sensitive and resistant mouse models, with and without ICB, using both flow cytometry and RNA sequencing techniques, and have found differences in myeloid and T cell infiltrate into the tumor microenvironment, suggesting that ADAM17 may regulate the tumor microenvironment landscape. We also have in vitro data suggesting that hypoactive variants of ADAM17 may reduce immune cell secretion of Tumor Necrosis Factor Alpha (TNFalpha) and TNFalpha induced cell death in specific immune cell types. TMI-2 is safe in humans, and this study provides support for targeting ADAM17 as a therapeutic target for patients who harbor ICB resistant cancers. The study also provides invaluable insights into the cell-type specific consequences of ADAM17 activity in tumor biology and highlights the need to consider patient genetics when applying ICB therapy.
利益披露 Disclosure
J. P. Heiserman, None..
D. Li, None..
T. Desai, None..
S. Chen, None.