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

• DOI: 10.1073/pnas.2105323118
• Publication Date: 2021-11-01T20:55:47Z
• Authors: William W. Ho; Igor L. Gomes-Santos; Shuichi Aoki; Meenal Datta; Kosuke Kawaguchi; Nilesh P. Talele; Sylvie Roberge; Jun Ren; Hao Liu; Ivy X. Chen; Patrik Andersson; Sampurna Chatterjee; Ashwin S. Kumar; Zohreh Amoozgar; Qixian Zhang; Peigen Huang; Mei Rosa Ng; Vikash P. Chauhan; Lei Xu; Dan G. Duda; Jeffrey W. Clark; Mikael J. Pittet; Dai Fukumura; Rakesh K. Jain
• Keywords: Male; 0303 health sciences; info:eu-repo/classification/ddc/616.07; Dendritic Cells; Biological Sciences; cancer immunotherapy; immune checkpoint blockade; mismatch repair–proficient colorectal cancer; orthotopic tumor model; tumor immune microenvironment; DNA Mismatch Repair; 3. Good health; Mice, Inbred C57BL; Interferon-gamma; Mice; 03 medical and health sciences; Liver Neoplasms, Experimental; info:eu-repo/classification/ddc/616; Cell Line, Tumor; Animals; Humans; Drug Screening Assays, Antitumor; Colorectal Neoplasms; Immune Checkpoint Inhibitors

Significance 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.