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

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 (FIt3L) 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 immuno-therapies against pMMR CRC.

Automated summary

Liver metastasis of mismatch repair-proficient (pMMR) CRCs is unresponsive to immune checkpoint blockade (ICB) therapy, while the same tumors are sensitive to ICB therapy when grown subcutaneously. Dendritic cells play a crucial role in increasing the efficacy of immuno-therapies against pMMR CRC liver metastases, as evidenced by increased infiltration and improved survival in mouse models. Compared to subcutaneous tumors, orthotopic liver metastases of pMMR CRCs show a paucity of activated T cells and dendritic cells, indicating the importance of utilizing orthotopic tumor models in guiding human clinical trials.