Dendritic cell paucity in mismatch repair–proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy
Abstract
Immune checkpoint blockade (ICB) has been efficacious in several cancer types. However, mismatch repair–proficient (pMMR) metastatic colorectal cancer (CRC), ∼95% of total metastatic CRC cases, typically does not respond to ICB. Here, we show that orthotopic liver metastasis mouse models of pMMR CRC cell lines are unresponsive to ICB and recapitulate the resistance of human disease, unlike subcutaneous tumors of the same cell lines. We also show that just like the human disease, orthotopic pMMR CRC liver metastases have a paucity of T cells and dendritic cells, and that treatment with Flt3L sensitizes the liver metastases to ICB. Our findings highlight that orthotopic tumor models, and not subcutaneous models, should be used for preclinical studies of cancer immunotherapy.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 01, 2021
- Source ID
- 10.1073/pnas.2105323118
Entities
People
- Ashwin S Kumar
- Dai Fukumura
- Dan G Duda
- Hao Liu
- Igor L Gomes-Santos
- Ivy X. Chen
- Jeffrey W. Clark
- Jun Ren
- Kosuke Kawaguchi
- Lei Xu
- Meenal Datta
- Mei Rosa Ng
- Mikael Pittet
- Nilesh P. Talele
- Patrik Andersson
- Peigen Huang
- Qixian Zhang
- Rakesh Jain
- Sampurna Chatterjee
- Shuichi Aoki
- Sylvie Roberge
- Vikash P. Chauhan
- William W Ho
- Zohreh Amoozgar
Organizations
- Congressionally Directed Medical Research Programs
- Geneva University Hospitals
- Harvard Medical School
- Harvard University
- Ludwig Institute for Cancer Research
- Massachusetts Institute of Technology
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- National Institute of Neurological Disorders and Stroke
- University of Geneva