A110:抗pd1免疫检查点阻断的有效性涉及肿瘤微环境中髓系和淋巴系亚群的协同相互作用

Sjoerd T. T. Schetters, Y. Kooyk
{"title":"A110:抗pd1免疫检查点阻断的有效性涉及肿瘤微环境中髓系和淋巴系亚群的协同相互作用","authors":"Sjoerd T. T. Schetters, Y. Kooyk","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A110","DOIUrl":null,"url":null,"abstract":"Suppression of the immune system by solid malignancies has proven to be a driving force of tumor development and an effective target for therapeutic intervention. The suppression of cytolytic T-cells by inhibitory receptors like PD1 can be blocked by antagonistic antibodies, reinvigorating suppressed antitumor responses. Nonetheless, only a minority of patients show clinical benefit. It is becoming clear the efficacy of checkpoint blockade relies on many factors, including pretreatment conditions, collaboration between innate and adaptive immune cells and immune-architecture of the tumor microenvironment (TME). To investigate this, we studied the immune profiles of the PD1-unresponsive murine B16 melanoma and PD1-responsive MC38 colorectal carcinoma models, systemically and in the TME before and during treatment. By using high-dimensional flow cytometry and unsupervised clustering analyses based on immune checkpoints, we show comparable early establishment of heterogeneity of tumor-infiltrating CD8+ and CD4+ T-cells. However, PD1-responsive MC38 tumor shows correlations in abundance between specific CD8+ T-cell, NK cells and myeloid subsets before checkpoint blockade treatment, while the PD1-unresponsive B16 tumors do not show lymphoid-myeloid codependences. Interestingly, the abundance of monocyte-derived dendritic cells did not increase upon anti-PD1 treatment but instead showed abundance correlation with PD1 CD4+ and CD8+ T-cells, suggesting a putative interaction. The unresponsive B16 tumors showed increased correlation of cDC1 and cDC2 with Foxp3+ regulatory T-cells. We have visualized these putative interactions within the myeloid and lymphoid population in the changing immune-architecture of the TME, using multiplex fluorescence and confocal microscopy. We show heterogeneity and interactive hotspots during immune checkpoint blockade and postulate that successful anti-PD1 treatment requires the location-dependent cooperation of specific myeloid and lymphoid subsets in the TME. Citation Format: Sjoerd Schetters, Yvette Van Kooyk. Efficacy of anti-PD1 immune checkpoint blockade involves the cooperative interaction of myeloid and lymphoid subpopulations in the tumor microenvironment [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 A110.","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 A110: Efficacy of anti-PD1 immune checkpoint blockade involves the cooperative interaction of myeloid and lymphoid subpopulations in the tumor microenvironment\",\"authors\":\"Sjoerd T. T. Schetters, Y. Kooyk\",\"doi\":\"10.1158/2326-6074.CRICIMTEATIAACR18-A110\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Suppression of the immune system by solid malignancies has proven to be a driving force of tumor development and an effective target for therapeutic intervention. The suppression of cytolytic T-cells by inhibitory receptors like PD1 can be blocked by antagonistic antibodies, reinvigorating suppressed antitumor responses. Nonetheless, only a minority of patients show clinical benefit. It is becoming clear the efficacy of checkpoint blockade relies on many factors, including pretreatment conditions, collaboration between innate and adaptive immune cells and immune-architecture of the tumor microenvironment (TME). To investigate this, we studied the immune profiles of the PD1-unresponsive murine B16 melanoma and PD1-responsive MC38 colorectal carcinoma models, systemically and in the TME before and during treatment. By using high-dimensional flow cytometry and unsupervised clustering analyses based on immune checkpoints, we show comparable early establishment of heterogeneity of tumor-infiltrating CD8+ and CD4+ T-cells. However, PD1-responsive MC38 tumor shows correlations in abundance between specific CD8+ T-cell, NK cells and myeloid subsets before checkpoint blockade treatment, while the PD1-unresponsive B16 tumors do not show lymphoid-myeloid codependences. Interestingly, the abundance of monocyte-derived dendritic cells did not increase upon anti-PD1 treatment but instead showed abundance correlation with PD1 CD4+ and CD8+ T-cells, suggesting a putative interaction. The unresponsive B16 tumors showed increased correlation of cDC1 and cDC2 with Foxp3+ regulatory T-cells. We have visualized these putative interactions within the myeloid and lymphoid population in the changing immune-architecture of the TME, using multiplex fluorescence and confocal microscopy. We show heterogeneity and interactive hotspots during immune checkpoint blockade and postulate that successful anti-PD1 treatment requires the location-dependent cooperation of specific myeloid and lymphoid subsets in the TME. Citation Format: Sjoerd Schetters, Yvette Van Kooyk. Efficacy of anti-PD1 immune checkpoint blockade involves the cooperative interaction of myeloid and lymphoid subpopulations in the tumor microenvironment [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 A110.\",\"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-A110\",\"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-A110","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

实体恶性肿瘤对免疫系统的抑制已被证明是肿瘤发展的驱动力和治疗干预的有效靶点。抑制受体如PD1对细胞溶解性t细胞的抑制可以被拮抗抗体阻断,从而使抑制的抗肿瘤反应重新活跃起来。然而,只有少数患者表现出临床获益。检查点阻断的有效性取决于许多因素,包括预处理条件、先天和适应性免疫细胞之间的协作以及肿瘤微环境(TME)的免疫结构,这一点越来越清楚。为了研究这一点,我们研究了pd1无应答的小鼠B16黑色素瘤和pd1应答的MC38结直肠癌模型在治疗前和治疗期间的全身和TME的免疫谱。通过使用高维流式细胞术和基于免疫检查点的无监督聚类分析,我们显示了肿瘤浸润性CD8+和CD4+ t细胞的早期异质性。然而,在检查点阻断治疗前,pd1应答的MC38肿瘤显示特异性CD8+ t细胞、NK细胞和髓细胞亚群之间存在丰富的相关性,而pd1无应答的B16肿瘤不显示淋巴-髓细胞共依赖性。有趣的是,单核细胞来源的树突状细胞的丰度在抗PD1治疗后并没有增加,而是与PD1 CD4+和CD8+ t细胞的丰度相关,这表明可能存在相互作用。无应答的B16肿瘤显示cDC1和cDC2与Foxp3+调节性t细胞的相关性增加。我们利用多重荧光和共聚焦显微镜观察了骨髓和淋巴细胞群体在TME免疫结构变化中的这些假定的相互作用。我们在免疫检查点阻断过程中发现了异质性和相互作用热点,并假设成功的抗pd1治疗需要TME中特定髓细胞和淋巴细胞亚群的位置依赖性合作。引文格式:Sjoerd Schetters, Yvette Van Kooyk。抗pd1免疫检查点阻断的有效性涉及肿瘤微环境中髓系和淋巴系亚群的协同相互作用[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,2019;7(2增刊):摘要nr A110。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Abstract A110: Efficacy of anti-PD1 immune checkpoint blockade involves the cooperative interaction of myeloid and lymphoid subpopulations in the tumor microenvironment
Suppression of the immune system by solid malignancies has proven to be a driving force of tumor development and an effective target for therapeutic intervention. The suppression of cytolytic T-cells by inhibitory receptors like PD1 can be blocked by antagonistic antibodies, reinvigorating suppressed antitumor responses. Nonetheless, only a minority of patients show clinical benefit. It is becoming clear the efficacy of checkpoint blockade relies on many factors, including pretreatment conditions, collaboration between innate and adaptive immune cells and immune-architecture of the tumor microenvironment (TME). To investigate this, we studied the immune profiles of the PD1-unresponsive murine B16 melanoma and PD1-responsive MC38 colorectal carcinoma models, systemically and in the TME before and during treatment. By using high-dimensional flow cytometry and unsupervised clustering analyses based on immune checkpoints, we show comparable early establishment of heterogeneity of tumor-infiltrating CD8+ and CD4+ T-cells. However, PD1-responsive MC38 tumor shows correlations in abundance between specific CD8+ T-cell, NK cells and myeloid subsets before checkpoint blockade treatment, while the PD1-unresponsive B16 tumors do not show lymphoid-myeloid codependences. Interestingly, the abundance of monocyte-derived dendritic cells did not increase upon anti-PD1 treatment but instead showed abundance correlation with PD1 CD4+ and CD8+ T-cells, suggesting a putative interaction. The unresponsive B16 tumors showed increased correlation of cDC1 and cDC2 with Foxp3+ regulatory T-cells. We have visualized these putative interactions within the myeloid and lymphoid population in the changing immune-architecture of the TME, using multiplex fluorescence and confocal microscopy. We show heterogeneity and interactive hotspots during immune checkpoint blockade and postulate that successful anti-PD1 treatment requires the location-dependent cooperation of specific myeloid and lymphoid subsets in the TME. Citation Format: Sjoerd Schetters, Yvette Van Kooyk. Efficacy of anti-PD1 immune checkpoint blockade involves the cooperative interaction of myeloid and lymphoid subpopulations in the tumor microenvironment [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 A110.
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
×
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
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
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 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信