An American-Swiss team deciphers why colorectal cancers are resistant to immunotherapies, and proposes a new potentially effective therapeutic combination.
Immune checkpoint blockade therapy, a recent immunotherapeutic strategy, has revolutionized cancer treatment in recent years. More than half of all cases of metastatic melanoma, once incurable, can now be cured. However, in all cancers, this therapy is only effective in less than 15% of patients. Colorectal cancer, the second most common cause of cancer-related death in the world, remains particularly resistant to this treatment, especially when the disease spreads to the liver. By studying the composition of immune cells present in colorectal cancer liver metastases, scientists from the University of Geneva (UNIGE) and the Massachusetts General Hospital (MGH) have found that these tumors lack dendritic cells, immune cells whose antitumor power is essential for the immune system to act. By increasing the presence of dendritic cells in tumors, immunotherapies could therefore be more effective. This work is published in the Proceedings of the National Academy of Sciences (PNAS) of the United States.
One of the main causes of death of people with colorectal cancer is the development of liver metastases. However, only 5% of cases respond to immune checkpoint therapy (ICB), an immunotherapeutic strategy that is very effective in other types of cancer.
“Colorectal cancer is the second leading cause of cancer-related death in the U.S. and worldwide,” says Rakesh K. Jain, director of the E.L. Steele Laboratories for Tumor Biology at MGH, who led this work with Mikaël Pittet, ISREC Foundation Chair in Immuno-Oncology in the Department of Pathology and Immunology and the Center for Translational Research in Onco-Hematology at the UNIGE Faculty of Medicine, a member of the Ludwig Institute for Cancer Research, and a member of the Swiss Cancer Centre Léman. “It is therefore urgent to better understand their resistance mechanisms to better fight them.”
Tumor location is key
The scientists studied different colorectal cancer cell lines in mice to see how they responded to ICB therapy. “In most studies, the tumor cell lines are injected under the skin of the mice, where they grow as subcutaneous tumors,” explains Mikaël Pittet, “but it turns out that these subcutaneous tumors respond well to ICB therapy, in contrast to what is observed in patients. This shows that experimental models must be refined to understand the immune mechanisms involved in cancer in all their subtlety.”
To understand this discrepancy, the research team studied mice in which cancer develops in the colon before metastasizing to the liver, as in humans. And this time, the cancer cells showed great resistance to ICB therapy just like the human cells. “Our results show how the environment in which cancer cells evolve can influence the effectiveness of immunotherapy, and why this must be taken into account in order to discover effective treatments,” explains Mikaël Pittet.
And in the liver?
Primary colorectal tumors can usually be surgically removed, but the resulting liver metastases are the main cause of death. But what are the mechanisms by which liver metastases are resistant to BCI therapy? The composition of the immune cells present in these metastases, compared with that of subcutaneously growing colorectal cancer, provided the explanation. “The major difference is the absence of dendritic cells in liver metastases, which are immune system cells necessary for the activation of cytotoxic T cells,” says Mikaël Pittet, “but this is precisely the biological mechanism on which ICB therapy is based. The scarcity of dendritic cells would thus explain the inefficiency of this therapy.” The same phenomenon was observed in mice and patients.
Promoting dendritic cell growth
To increase the number of dendritic cells in liver metastases of colorectal cancer, scientists administered to mice a growth factor (Flt3L) that promotes the production of dendritic cells. This treatment resulted in a significant improvement in the efficacy of ICB immunotherapies. These results highlight the possibility of developing new therapies for metastatic colorectal cancer by combining Flt3L growth factor and ICB therapy. Clinical evaluations will now be conducted to confirm these very encouraging initial results in humans.
Legend: Representation of a dendritic cell (yellow) that activates T lymphocytes (blue)
Reference: https://doi.org/10.1016/j.cell.2021.07.015.
See also: October 18, 2021: Radio interview for the RTS, “Emission CQFD”, entitled “Des immunothérapies efficaces contre les cancers colorectaux”.
