摘要:黑色素瘤对前吞噬细胞信号上调和CD47阻断表现出进化上保守的抗性

K. L. Anderson, K. Snyder, D. Ito, Debra C. Lins, L. Mills, K. Weiskopf, N. G. Ring, A. Ring, Y. Shimizu, M. Mescher, I. Weissman, J. Modiano
{"title":"摘要:黑色素瘤对前吞噬细胞信号上调和CD47阻断表现出进化上保守的抗性","authors":"K. L. Anderson, K. Snyder, D. Ito, Debra C. Lins, L. Mills, K. Weiskopf, N. G. Ring, A. Ring, Y. Shimizu, M. Mescher, I. Weissman, J. Modiano","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A051","DOIUrl":null,"url":null,"abstract":"Therapeutic activation of macrophage phagocytosis has the ability to restrain tumor growth through phagocytic clearance of tumor cells and activation of the adaptive immune response. Our objective for this study was to evaluate the effects of modulating pro- and anti-phagocytic pathways in malignant melanoma. In order to identify evolutionarily conserved mechanisms of resistance that may be important for melanoma cell survival, we utilized a multispecies approach and examined the phagocytosis of human, mouse, and dog melanoma cells in vitro. We blocked the interaction between CD47 on tumor cells and SIRPα on macrophages using anti-CD47 monoclonal antibodies, SIRPα mimotopes, and a soluble fusion protein of the SIRPα extracellular domain. In all cases, we confirmed that these reagents blocked >85% of the maximum binding of CD47 to recombinant SIRPα. We observed that melanoma cells from all three species displayed unexpected resistance to phagocytosis that could not be fully mitigated by blockade of the “don’t eat me” signal CD47 or by chemotherapeutic enhancement of known “eat me” signals. In vitro, CD47 blockade minimally enhanced phagocytosis of melanoma cells, and loss of CD47 expression did not increase sensitivity to phagocytosis. In vivo, CD47 blockade enhanced the proliferation of tumor-specific CD8+ T-cells, but this response failed to inhibit tumor growth. Resistance to phagocytosis was not mediated by soluble factors, as phagocytosis of melanoma cells was not enhanced by inhibition of secretory pathways, and phagocytosis of sensitive lymphoma tumor cells was not impaired in the presence of melanoma cells or melanoma culture supernatants. siRNA-mediated knockdown of 47 prospective “don’t eat me” signals similarly did not enhance melanoma cell phagocytosis. Interestingly, in lymphoma cells, CD47 knockout alone did not enhance phagocytosis, suggesting that at least part of the pro-phagocytic effect of CD47 blockade is due to Fc receptor engagement. Restoration of CD47 expression in lymphoma cells re-established sensitivity to CD47 blockade. We conclude that melanoma cells possess an evolutionarily conserved resistance to macrophage phagocytosis. Further investigation will be needed to define and overcome the mechanisms that mediate melanoma cell resistance to innate immunity. Citation Format: Katie L. Anderson, Kristin M. Snyder, Daisuke Ito, Debra C. Lins, Lauren J. Mills, Kipp Weiskopf, Nan G. Ring, Aaron M Ring, Yoji Shimizu, Matthew F. Mescher, Irving L. Weissman, Jaime F. Modiano. Melanoma displays an evolutionarily conserved resistance to upregulation of prophagocytic signals and to CD47 blockade [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A051.","PeriodicalId":22141,"journal":{"name":"Tackling the Tumor Microenvironment: Beyond T-cells","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Abstract A051: Melanoma displays an evolutionarily conserved resistance to upregulation of prophagocytic signals and to CD47 blockade\",\"authors\":\"K. L. Anderson, K. Snyder, D. Ito, Debra C. Lins, L. Mills, K. Weiskopf, N. G. Ring, A. Ring, Y. Shimizu, M. Mescher, I. Weissman, J. Modiano\",\"doi\":\"10.1158/2326-6074.CRICIMTEATIAACR18-A051\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Therapeutic activation of macrophage phagocytosis has the ability to restrain tumor growth through phagocytic clearance of tumor cells and activation of the adaptive immune response. Our objective for this study was to evaluate the effects of modulating pro- and anti-phagocytic pathways in malignant melanoma. In order to identify evolutionarily conserved mechanisms of resistance that may be important for melanoma cell survival, we utilized a multispecies approach and examined the phagocytosis of human, mouse, and dog melanoma cells in vitro. We blocked the interaction between CD47 on tumor cells and SIRPα on macrophages using anti-CD47 monoclonal antibodies, SIRPα mimotopes, and a soluble fusion protein of the SIRPα extracellular domain. In all cases, we confirmed that these reagents blocked >85% of the maximum binding of CD47 to recombinant SIRPα. We observed that melanoma cells from all three species displayed unexpected resistance to phagocytosis that could not be fully mitigated by blockade of the “don’t eat me” signal CD47 or by chemotherapeutic enhancement of known “eat me” signals. In vitro, CD47 blockade minimally enhanced phagocytosis of melanoma cells, and loss of CD47 expression did not increase sensitivity to phagocytosis. In vivo, CD47 blockade enhanced the proliferation of tumor-specific CD8+ T-cells, but this response failed to inhibit tumor growth. Resistance to phagocytosis was not mediated by soluble factors, as phagocytosis of melanoma cells was not enhanced by inhibition of secretory pathways, and phagocytosis of sensitive lymphoma tumor cells was not impaired in the presence of melanoma cells or melanoma culture supernatants. siRNA-mediated knockdown of 47 prospective “don’t eat me” signals similarly did not enhance melanoma cell phagocytosis. Interestingly, in lymphoma cells, CD47 knockout alone did not enhance phagocytosis, suggesting that at least part of the pro-phagocytic effect of CD47 blockade is due to Fc receptor engagement. Restoration of CD47 expression in lymphoma cells re-established sensitivity to CD47 blockade. We conclude that melanoma cells possess an evolutionarily conserved resistance to macrophage phagocytosis. Further investigation will be needed to define and overcome the mechanisms that mediate melanoma cell resistance to innate immunity. Citation Format: Katie L. Anderson, Kristin M. Snyder, Daisuke Ito, Debra C. Lins, Lauren J. Mills, Kipp Weiskopf, Nan G. Ring, Aaron M Ring, Yoji Shimizu, Matthew F. Mescher, Irving L. Weissman, Jaime F. Modiano. Melanoma displays an evolutionarily conserved resistance to upregulation of prophagocytic signals and to CD47 blockade [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A051.\",\"PeriodicalId\":22141,\"journal\":{\"name\":\"Tackling the Tumor Microenvironment: Beyond T-cells\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2019-02-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Tackling the Tumor Microenvironment: Beyond T-cells\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A051\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Tackling the Tumor Microenvironment: Beyond T-cells","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A051","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

摘要

治疗性激活巨噬细胞吞噬作用可以通过吞噬清除肿瘤细胞和激活适应性免疫反应来抑制肿瘤生长。我们这项研究的目的是评估调节促和抗吞噬通路在恶性黑色素瘤中的作用。为了确定可能对黑色素瘤细胞存活很重要的进化保守的耐药机制,我们采用多物种方法,并在体外检测了人类、小鼠和狗黑色素瘤细胞的吞噬作用。我们利用抗CD47单克隆抗体、SIRPα模位和SIRPα胞外结构域的可溶性融合蛋白阻断肿瘤细胞上的CD47与巨噬细胞上的SIRPα的相互作用。在所有病例中,我们证实这些试剂阻断了>85%的CD47与重组SIRPα的最大结合。我们观察到,来自这三个物种的黑色素瘤细胞都表现出意想不到的对吞噬的抵抗,这种抵抗不能通过阻断“不要吃我”信号CD47或通过化疗增强已知的“吃我”信号来完全减轻。在体外,CD47阻断对黑色素瘤细胞的吞噬作用有最低限度的增强,CD47表达的缺失并没有增加对吞噬的敏感性。在体内,CD47阻断增强了肿瘤特异性CD8+ t细胞的增殖,但这种反应未能抑制肿瘤生长。对吞噬的抵抗不是由可溶性因子介导的,因为黑素瘤细胞的吞噬作用不会通过抑制分泌途径而增强,并且在黑素瘤细胞或黑素瘤培养上清存在时,敏感淋巴瘤肿瘤细胞的吞噬作用不会受损。sirna介导的47个“不要吃我”信号的敲除同样没有增强黑色素瘤细胞的吞噬作用。有趣的是,在淋巴瘤细胞中,单独敲除CD47并没有增强吞噬作用,这表明CD47阻断的促吞噬作用至少部分是由于Fc受体的参与。淋巴瘤细胞中CD47表达的恢复重建了对CD47阻断的敏感性。我们得出结论,黑色素瘤细胞具有对巨噬细胞吞噬的进化保守抗性。需要进一步的研究来确定和克服介导黑色素瘤细胞抵抗先天免疫的机制。引文格式:Katie L. Anderson, Kristin M. Snyder, Daisuke Ito, Debra C. Lins, Lauren J. Mills, Kipp Weiskopf, Nan G. Ring, Aaron M Ring, Yoji Shimizu, Matthew F. Mescher, Irving L. Weissman, Jaime F. Modiano。黑色素瘤对前吞噬细胞信号上调和CD47阻断表现出进化上保守的抗性[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约,纽约。费城(PA): AACR;癌症免疫学杂志2019;7(2增刊):摘要nr A051。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Abstract A051: Melanoma displays an evolutionarily conserved resistance to upregulation of prophagocytic signals and to CD47 blockade
Therapeutic activation of macrophage phagocytosis has the ability to restrain tumor growth through phagocytic clearance of tumor cells and activation of the adaptive immune response. Our objective for this study was to evaluate the effects of modulating pro- and anti-phagocytic pathways in malignant melanoma. In order to identify evolutionarily conserved mechanisms of resistance that may be important for melanoma cell survival, we utilized a multispecies approach and examined the phagocytosis of human, mouse, and dog melanoma cells in vitro. We blocked the interaction between CD47 on tumor cells and SIRPα on macrophages using anti-CD47 monoclonal antibodies, SIRPα mimotopes, and a soluble fusion protein of the SIRPα extracellular domain. In all cases, we confirmed that these reagents blocked >85% of the maximum binding of CD47 to recombinant SIRPα. We observed that melanoma cells from all three species displayed unexpected resistance to phagocytosis that could not be fully mitigated by blockade of the “don’t eat me” signal CD47 or by chemotherapeutic enhancement of known “eat me” signals. In vitro, CD47 blockade minimally enhanced phagocytosis of melanoma cells, and loss of CD47 expression did not increase sensitivity to phagocytosis. In vivo, CD47 blockade enhanced the proliferation of tumor-specific CD8+ T-cells, but this response failed to inhibit tumor growth. Resistance to phagocytosis was not mediated by soluble factors, as phagocytosis of melanoma cells was not enhanced by inhibition of secretory pathways, and phagocytosis of sensitive lymphoma tumor cells was not impaired in the presence of melanoma cells or melanoma culture supernatants. siRNA-mediated knockdown of 47 prospective “don’t eat me” signals similarly did not enhance melanoma cell phagocytosis. Interestingly, in lymphoma cells, CD47 knockout alone did not enhance phagocytosis, suggesting that at least part of the pro-phagocytic effect of CD47 blockade is due to Fc receptor engagement. Restoration of CD47 expression in lymphoma cells re-established sensitivity to CD47 blockade. We conclude that melanoma cells possess an evolutionarily conserved resistance to macrophage phagocytosis. Further investigation will be needed to define and overcome the mechanisms that mediate melanoma cell resistance to innate immunity. Citation Format: Katie L. Anderson, Kristin M. Snyder, Daisuke Ito, Debra C. Lins, Lauren J. Mills, Kipp Weiskopf, Nan G. Ring, Aaron M Ring, Yoji Shimizu, Matthew F. Mescher, Irving L. Weissman, Jaime F. Modiano. Melanoma displays an evolutionarily conserved resistance to upregulation of prophagocytic signals and to CD47 blockade [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A051.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
0
期刊最新文献
The Tumor Microenvironment: Methods and Protocols Abstract A113: Harnessing lymphoid organ neogenesis as a novel prognostic biomarker and therapeutic target Abstract A072: Calreticulin exposures by malignant blasts correlate with robust anticancer immunity and improved clinical outcome in AML patients Abstract A092: TAM receptors targeting unleashes antileukemic immunity and enables checkpoint blockade leading to eradication of leukemic cells Abstract A070: Virotherapy eradicates established melanoma by reprogramming the tumor microenvironment and engaging the adaptive immunity
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1