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: Immune checkpoint

Liver metastasis is a major cause of mortality for patients with colorectal cancer (CRC). Mismatch repair-proficient (pMMR) CRCs make up about 95% metastatic CRCs, and are unresponsive to immune checkpoint blockade (ICB) therapy. Here we show that mouse models orthotopic pMMR CRC liver accurately recapitulate the inefficacy ICB therapy in patients, whereas same tumors sensitive when grown subcutaneously. To reveal local, nonmalignant components determine sensitivity treatment, compared microenvironments cells as metastases subcutaneous tumors. We found paucity both activated T dendritic ICB-treated metastases, their tumor counterparts. Furthermore, treatment Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 ligand (Flt3L) plus increased cell infiltration into improved survival. Lastly, human microsatellite stable (MSS) primary have similar cells. These studies indicate models, but not should be used guide clinical trials. Our findings also posit antitumor can increase efficacy immunotherapies against CRC.