气候变化领域集成服务门户(CCPortal): Dendritic cell paucity in mismatch repair-proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy

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DOI	10.1073/pnas.2105323118
	Dendritic cell paucity in mismatch repair-proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy
	Ho W.W.; Gomes-Santos I.L.; Aoki S.; Datta M.; Kawaguchi K.; Talele N.P.; Roberge S.; Ren J.; Liu H.; Chen I.X.; Andersson P.; Chatterjee S.; Kumar A.S.; Amoozgar Z.; Zhang Q.; Huang P.; Ng M.R.; Chauhan V.P.; Xu L.; Duda D.G.; Clark J.W.; Pittet M.J.; Fukumura D.; Jain R.K.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:45
英文摘要	Liver metastasis is a major cause of mortality for patients with colorectal cancer (CRC). Mismatch repair-proficient (pMMR) CRCs make up about 95% of metastatic CRCs, and are unresponsive to immune checkpoint blockade (ICB) therapy. Here we show that mouse models of orthotopic pMMR CRC liver metastasis accurately recapitulate the inefficacy of ICB therapy in patients, whereas the same pMMR CRC tumors are sensitive to ICB therapy when grown subcutaneously. To reveal local, nonmalignant components that determine CRC sensitivity to treatment, we compared the microenvironments of pMMR CRC cells grown as liver metastases and subcutaneous tumors. We found a paucity of both activated T cells and dendritic cells in ICB-treated orthotopic liver metastases, when compared with their subcutaneous tumor counterparts. Furthermore, treatment with Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 ligand (Flt3L) plus ICB therapy increased dendritic cell infiltration into pMMR CRC liver metastases and improved mouse survival. Lastly, we show that human CRC liver metastases and microsatellite stable (MSS) primary CRC have a similar paucity of T cells and dendritic cells. These studies indicate that orthotopic tumor models, but not subcutaneous models, should be used to guide human clinical trials. Our findings also posit dendritic cells as antitumor components that can increase the efficacy of immunotherapies against pMMR CRC. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Cancer immunotherapy; Immune checkpoint blockade; Mismatch repair-proficient colorectal cancer; Orthotopic tumor model; Tumor immune microenvironment
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/238761
作者单位	Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States; Harvard-MIT Program in Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, United States; Department of Hematology/Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States; Department of Pathology and Immunology, University of Geneva, Geneva, CH-1211, Switzerland; Ludwig Institute for Cancer Research, Lausanne, 1005, Switzerland; Department of Oncology, Geneva University Hospitals, Geneva, CH-1211, Switzerland; Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
推荐引用方式 GB/T 7714	Ho W.W.,Gomes-Santos I.L.,Aoki S.,et al. Dendritic cell paucity in mismatch repair-proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy[J],2021,118(45).
APA	Ho W.W..,Gomes-Santos I.L..,Aoki S..,Datta M..,Kawaguchi K..,...&Jain R.K..(2021).Dendritic cell paucity in mismatch repair-proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy.Proceedings of the National Academy of Sciences of the United States of America,118(45).
MLA	Ho W.W.,et al."Dendritic cell paucity in mismatch repair-proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy".Proceedings of the National Academy of Sciences of the United States of America 118.45(2021).