Dendritic cell paucity in mismatch repair-proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy.

Details

Serval ID
serval:BIB_E44392371B42
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Dendritic cell paucity in mismatch repair-proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy.
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
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.
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Publication state
Published
Issued date
09/11/2021
Peer-reviewed
Oui
Volume
118
Number
45
Pages
e2105323118
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
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.
Keywords
cancer immunotherapy, immune checkpoint blockade, mismatch repair–proficient colorectal cancer, orthotopic tumor model, tumor immune microenvironment
Pubmed
Web of science
Open Access
Yes
Create date
09/11/2021 8:24
Last modification date
04/12/2021 6:36
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