Combinations of BRAF inhibitor and anti-PD-1/PD-L1 antibody improve survival and tumour immunity in an immunocompetent model of orthotopic murine anaplastic thyroid cancer.
Combinations of BRAF inhibitor and anti-PD-1/PD-L1 antibody improve survival and tumour immunity in an immunocompetent model of orthotopic murine anaplastic thyroid cancer.
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DOI：
10.1038/s41416-018-0296-2
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发表时间：
2018-11
影响因子：
8.8
通讯作者：
Parangi S
中科院分区：
文献类型：
--
作者：
Gunda V;Gigliotti B;Ndishabandi D;Ashry T;McCarthy M;Zhou Z;Amin S;Freeman GJ;Alessandrini A;Parangi S
间变性甲状腺癌（ATC）患者预后极差，尽管积极的多模式治疗。ATC具有BRAFV600E突变的高流行率，并与免疫抑制微环境有关；我们之前证明了BRAF抑制剂和检查点抑制剂联合免疫治疗可协同减少原位ATC免疫活性小鼠模型中的肿瘤体积。我们再次利用我们的ATC小鼠模型来评估BRAFV600E抑制剂PLX4720与抗pd - l1或抗pd -1抗体联合使用对生存的影响，并在最大治疗反应和肿瘤再生期间对淋巴细胞和髓系细胞进行免疫细胞谱分析。联合治疗显著提高了小鼠存活率。最大的肿瘤减少与CD8+ T细胞和NK细胞的数量和细胞毒性的增加，以及m1极化肿瘤相关巨噬细胞（TAM）的增加和髓源性抑制样细胞的减少有关。在持续的联合治疗2-3周后，肿瘤发生再生，并且与tam减少和m2极化急剧增加最显著相关。PLX4720与抗pd - l1 /PD-1抗体联合使用可显著减少ATC小鼠肿瘤体积，延长生存期，提高抗肿瘤免疫谱。肿瘤生长不可避免地复发，并表现出免疫抑制肿瘤微环境的重新出现。
Patients with anaplastic thyroid cancer (ATC) have an extremely poor prognosis despite aggressive multimodal therapy. ATC has a high prevalence of BRAFV600E mutations and is associated with an immunosuppressive microenvironment; we previously demonstrated that the combination of BRAF inhibitor and checkpoint inhibitor immunotherapy synergistically reduce tumour volume in an immunocompetent mouse model of orthotopic ATC. We again utilised our mouse model of ATC to assess the combination of BRAFV600E inhibitor PLX4720 and anti-PD-L1 or anti-PD-1 antibody on survival, and performed immune cell profiling of lymphoid and myeloid-lineage cells during maximal treatment response and tumour regrowth. Combination therapy dramatically improved mouse survival. Maximal tumour reduction was associated with increases in the number and cytotoxicity of CD8+ T cells and NK cells, as well as increases in mostly M1-polarised tumour-associated macrophages (TAM) and decreases in myeloid-derived suppressor-like cells. Regrowth of tumour occurred after 2–3 weeks of ongoing combination therapy, and was most significantly associated with decreased TAMs and a dramatic increase in M2-polarisation. Combination of PLX4720 and anti-PD-L1/PD-1 antibody dramatically reduced tumour volume, prolonged survival and improved the anti-tumour immune profile in murine ATC. Tumour growth inevitably recurred and demonstrated re-emergence of an immunosuppressive tumour microenvironment.
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影响因子：
16.6
作者：
Dushyanthen S;Teo ZL;Caramia F;Savas P;Mintoff CP;Virassamy B;Henderson MA;Luen SJ;Mansour M;Kershaw MH;Trapani JA;Neeson PJ;Salgado R;McArthur GA;Balko JM;Beavis PA;Darcy PK;Loi S
通讯作者：
Loi S
DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
DOI：
10.1634/theoncologist.2010-0317
发表时间：
2011
期刊：
The oncologist
影响因子：
--
作者：
Nucera C;Nehs MA;Nagarkatti SS;Sadow PM;Mekel M;Fischer AH;Lin PS;Bollag GE;Lawler J;Hodin RA;Parangi S
通讯作者：
Parangi S
影响因子：
3.7
作者：
Caillou B;Talbot M;Weyemi U;Pioche-Durieu C;Al Ghuzlan A;Bidart JM;Chouaib S;Schlumberger M;Dupuy C
通讯作者：
Dupuy C
影响因子：
3.9
作者：
Ryder M;Ghossein RA;Ricarte-Filho JC;Knauf JA;Fagin JA
通讯作者：
Fagin JA