Anti-PD-1 therapy redirects macrophages from an M2 to an M1 phenotype inducing regression of OS lung metastases.
Anti-PD-1 therapy redirects macrophages from an M2 to an M1 phenotype inducing regression of OS lung metastases.
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DOI：
10.1002/cam4.1518
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发表时间：
2018-06
期刊：
影响因子：
4
通讯作者：
Kleinerman ES
中科院分区：
文献类型：
--
作者：
Dhupkar P;Gordon N;Stewart J;Kleinerman ES
骨肉瘤(OS)肺转移转化为患者较差的存活率。PD-1-PD-L1通路在OS中NK细胞和/或巨噬细胞中的作用尚不清楚。我们研究了抗PD-1抗体在OS肺转移中的作用，以及NK细胞和/或巨噬细胞在抗PD-1反应中的作用。采用人LM7OS小鼠模型。免疫组织化学染色(PD-L1、caspase-3、Ki-67、NK细胞、巨噬细胞)，Western blotting检测OS肺肿瘤(p-STAT3、p-ERK1/2)。用流式细胞仪检测NK细胞和巨噬细胞。分别用抗asialo GM1抗体和封闭体法去除NK细胞和巨噬细胞。PD-L1在人OS细胞和OS患者肺转移瘤中均有表达。抗PD1抗体可显著减少OS肺转移数目，促进肿瘤细胞凋亡，抑制肿瘤细胞增殖，阻断p-STAT-3/p-ERK1/2信号转导通路。OS肺癌中NK细胞和巨噬细胞表达PD-1，抗PD1抗体可增加NK细胞和巨噬细胞对肿瘤的侵袭。抗肿瘤的M1巨噬细胞数量增加，促炎症的M2巨噬细胞数量减少。NK细胞耗竭不影响抗PD-1的疗效，提示NK细胞不是直接参与的。然而，巨噬细胞的去除显著降低了抗PD1的效果，证实了它们在抗PD-1抗OS肺转移中的作用。我们的研究结果表明，抗PD1抗体可通过激活肿瘤M1巨噬细胞和减少M2巨噬细胞而导致OS肺转移的消退。鉴于M1巨噬细胞与OS患者预后的相关性，我们提供了一种新的阻断PD-1的机制，并为未来OS患者抗PD-1抗体的临床试验奠定了基础。
Osteosarcoma (OS) pulmonary metastasis translates into poor patient survival. The implication of PD‐1‐PD‐L1 pathway in the context of NK cells and/or macrophages in OS is unknown. We investigated the effect of anti‐PD‐1 in OS lung metastasis and the role of NK cells and/or macrophages in anti‐PD‐1 responses. A human LM7 OS mouse model was used. Immunohistochemistry for tissues (PD‐L1, caspase‐3, Ki‐67, NK cells, macrophages), and Western blotting for OS lung tumors (p‐Stat3, p‐Erk1/2) was performed. NK and macrophages were assessed using flow cytometry. NK cell and macrophage depletion were conducted using anti‐asialo GM1 and clodrosome, respectively. PD‐L1 expression was observed in human OS cells and OS patient lung metastases. Anti‐PD1 antibody led to a significant decrease in the number of OS lung metastases, enhanced tumor apoptosis, decreased tumor cell proliferation, and p‐STAT‐3/p‐Erk1/2 signaling blockade in OS lung tumors. NK cells and macrophages in OS lung tumors expressed PD‐1 and anti‐PD1 increased NK cell and macrophage tumor infiltration. Increased numbers of antitumor M1 macrophages and decreased pro‐inflammatory M2 macrophages were seen. NK depletion did not affect therapeutic effect of anti‐PD‐1, suggesting that NK cells were not directly involved. However, macrophage depletion significantly compromised anti‐PD1 efficacy, confirming their role in efficacy of anti‐PD‐1 against OS lung metastasis. Our findings suggest that OS lung metastases regression by anti‐PD1 can be attributed to activated tumor M1 macrophages and reduced M2 macrophages. Owing to the co‐relation of M1 macrophages with OS patient outcome, we provide a novel mechanism of PD‐1 blockade and a basis for future clinical trials for anti‐PD‐1 antibodies in OS.
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影响因子：
3.2
作者：
Guma, Sergei R.;Lee, Dean A.;Yu, Ling;Gordon, Nancy;Hughes, Dennis;Stewart, John;Wang, Wei Lien;Kleinerman, Eugenie S.
通讯作者：
Kleinerman, Eugenie S.
DOI：
10.1158/1078-0432.ccr-16-3122
发表时间：
2017-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Brown JM;Recht L;Strober S
通讯作者：
Strober S
DOI：
10.1073/pnas.0809422106
发表时间：
2009-04-14
影响因子：
11.1
作者：
Huang, Xin;Venet, Fabienne;Ayala, Alfred
通讯作者：
Ayala, Alfred
影响因子：
4.4
作者：
Iwai, Y;Terawaki, S;Honjo, T
通讯作者：
Honjo, T
影响因子：
8.8
作者：
Abiko, K.;Matsumura, N.;Hamanishi, J.;Horikawa, N.;Murakami, R.;Yamaguchi, K.;Yoshioka, Y.;Baba, T.;Konishi, I.;Mandai, M.
通讯作者：
Mandai, M.