Ho et al. studied ICB resistance mechanisms of mismatch repair-proficient colorectal cancer (pMMR CRC). pMMR CRC tumors responded to ICB in s.c., but not orthotopic (colon or liver metastasis) models, where they contained fewer activated T cells and DCs. Co-administering FLT3 ligand with ICB increased DC and CD8+ T cell numbers in liver metastases and mouse survival, but ICB had variable additional impact on DC numbers and survival alongside IFNα or radiation. In CRC patients, gene scores for T cell activation and DCs were reduced in liver metastases and pMMR primary tumors compared to microsatellite instability-high CRC.
Contributed by Alex Najibi
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.
Author Info: (1) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. Department of Chemical Engineering,
Author Info: (1) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139. (2) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. (3) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. (4) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. (5) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. (6) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. (7) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. (8) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. (9) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. (10) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. (11) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. (12) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. (13) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. Harvard-MIT Program in Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139. (14) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. (15) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. (16) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. (17) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. (18) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. (19) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. (20) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. (21) Department of Hematology/Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. (22) Department of Pathology and Immunology, University of Geneva, CH-1211 Geneva, Switzerland; mikael.pittet@unige.ch dai@steele.mgh.harvard.edu jain@steele.mgh.harvard.edu. Ludwig Institute for Cancer Research, 1005 Lausanne, Switzerland. Department of Oncology, Geneva University Hospitals, CH-1211 Geneva, Switzerland. Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. (23) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; mikael.pittet@unige.ch dai@steele.mgh.harvard.edu jain@steele.mgh.harvard.edu. (24) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; mikael.pittet@unige.ch dai@steele.mgh.harvard.edu jain@steele.mgh.harvard.edu.
