Immunotherapy, the treatment that stimulates the body's own defenses to locate and destroy malignant cells, is revolutionizing the approach to some types of cancer, such as melanoma.
However, in other tumors, this therapy does not achieve the expected results. This is the case with metastatic colorectal cancer, where the vast majority of patients do not respond to immunotherapy.
This week, a study led by researchers from the Institute for Research in Biomedicine (IRB Barcelona) and the National Center for Genomic Analysis (CNAG) provides new insights into why this lack of response occurs. Additionally, the study also proposes strategies to overcome this obstacle.
The research shows that colorectal cancer is able to create a double barrier to prevent the action of immune system cells, blocking the effect of immunotherapy.
The details of the study, published in the latest issue of Nature Genetics, demonstrate that a hormone called TGF-beta plays a key role in creating this double barrier.
For immunotherapy to work, three aspects must be present. Firstly, a sufficient number of a specific type of defensive cells, T lymphocytes, must reach the tumor from the bloodstream. Then, these lymphocytes must be able to multiply within the tumor, as well as move freely to locate and eliminate cancer cells, explains Elena Sancho, a researcher in Eduard Batlle's laboratory who, along with Alejandro Prados from IRB and Holger Heyn from CNAG, led the study.
In the case of colorectal cancer, these conditions are not met because the tumor is able to manipulate the environment in its favor, blocking the immune response through a double barrier. On one hand, through the hormone TGF-beta, it prevents a sufficient number of T lymphocytes from reaching the tumor. Additionally, using the same hormone, it also blocks the expansion of the few T cells that manage to infiltrate the tumor.
This hormone acts, first, as a 'no entry' signal to prevent enough defensive cells from arriving. Furthermore, TGF-beta also "modifies macrophages in the tumor microenvironment to secrete a protein, osteopontin, which prevents the multiplication of the few T cells that manage to enter the tumor," says Sancho.
Together, these barriers make the tumor practically invisible to the immune system.
The study combines experimental models of metastasis in mice with analyses of patient tumors.
The team has studied the mechanism in colorectal cancer but believes that the findings may also be useful in understanding why immunotherapy does not work in a high percentage of patients with other tumors, such as liver or pancreatic cancer.
The project has received funding from the Olga Torres Foundation, "la Caixa" Foundation, World Wide Cancer Research, the European Research Council (ERC Advanced Grant), the Spanish Association Against Cancer (AECC) through the Excellence Program and other research grants, the Ministry of Science, Innovation and Universities, La Marató de TV3, and the Agency for Management of University and Research Grants (AGAUR).