News Releases

Study led by Ludwig researchers identifies strategy to overcome colorectal cancer resistance to immunotherapy

NOVEMBER 9, 2021, NEW YORK – A study led by Ludwig Harvard investigator Rakesh Jain, his Harvard colleague Dai Fukumura and Ludwig Lausanne’s Mikaël Pittet provides insights on why colorectal cancers are frequently unresponsive to immunotherapy and offers a strategy to overcome their resistance.

Most colorectal cancers that spread to the liver resist immune checkpoint blockade (ICB). Yet when Jain, Fukumura, Pittet and colleagues injected colorectal cancer cells under the skin in the hind flank of mice—a common procedure in cancer research—the resulting tumors responded well to ICB therapy. To explore this discrepancy, the investigators generated orthotopic (meaning “the normal place in the body”) mouse models by injecting the cancer cells in relevant anatomical sites, including the colon and the liver, where such cancers often metastasize.

The researchers reported in the November 9 issue of the Proceedings of the National Academy of Sciences that these mouse models are profoundly resistant to immune checkpoint inhibitors, illustrating how the environment in which cancer cells grow can influence the effectiveness of immunotherapy.

The researchers showed that in the orthoptic models, liver metastases lack immune cells known as dendritic cells, which direct and activate the immune system’s cancer-targeting cytotoxic T lymphocytes (CTLs). Tumors from patients were similarly deficient in dendritic cells and activated CTLs. When the team augmented the number of dendritic cells in liver metastases using a growth factor, Flt3L, the number of CTLs within the tumors increased dramatically and the cancer became newly responsive to ICB therapy.

“Our study highlights the importance of orthotopic tumor models in immunotherapy studies and underscores the relevance of dendritic cells for effective immune checkpoint blockade,” said Pittet, who is also ISREC Foundation Chair in Immuno-oncology at the University of Geneva. “It also points to the possibility of developing new therapies that could be effective in controlling resistant colorectal cancer.”

Jain is also director of the E.L. Steele Laboratories for Tumor Biology at Massachusetts General Hospital (MGH) and the Andrew Werk Cook Professor of Radiation Oncology at Harvard Medical School (HMS).

The MGH release from which this summary is derived can be found here.


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