- A team headed by ICREA researcher Eduard Batlle discovers that immune system-stimulating treatments combined with a TGF-beta inhibitor are effective against colon cancer.
- The researchers developed a mouse model that mimics advanced human colon cancer. This model has allowed them to study the immune system response for the first time.
Barcelona, Wed. 14 February 2018.- In a short space of time, immunotherapy, that is to say therapies based on stimulating the immune system against cancer cells, has become a powerful approach to treat cancers such as melanoma and lung cancer. However, to date, most colon tumours appeared to be unresponsive to this kind of therapy. Given this observation, it was hypothesized that this kind of tumour was simply invisible to the immune system. In a study published today in the journal Nature, a team headed by ICREA researcher,
Eduard Batlle, at the Institute for Research in Biomedicine (IRB Barcelona),
explains that the hormone TGF-betais responsible for the “blindness” of the immune system to colon cancer cells“The few clinical immunotherapy trials done in patients with the most common subtype of colon cancer were not giving good results and we didn’t understand why this was happening,” explains
Eduard Batlle.By inhibiting the activity of TGF-beta, the cells of the immune system infiltrate and recognise the tumour, fight the cancer, and even stop colon tumours from metastasizing to the liver and lung in a preclinical mouse model that mimics the human disease
In addition, and more importantly, the researchers have demonstrated that the combination of a TGF-beta inhibitor with available immunotherapies boost the anti-tumour effect allowing the immune system to efficiently eliminate already established metastases, which would otherwise kill the individual in a question of weeks.
Model that mimics aggressive human colon cancer
The scientist
Daniele Tauriello, postdoctoral fellow and first author of the article, induced four of the most common mutations present in advanced human colon tumours in mice.
“The development of the animal model took us four years but we hit the nail on the head,”, he says.
After confirming the similarity of the mouse tumours with those in humans, they built a biobank of tumour organoids—3D mini-tumours— to then graft them in a controlled manner in immunocompetent mice.
“For studies of the immune system, the tumour has to be of mouse origin otherwise the animal would reject it,”he explains This animal model, which mimics the main features of metastatic colon cancer in patients, allowed the researchers to examine how cancer cells evade the immune system.
Beyond colon cancer
Around 40 to 50% of colon cancer patients relapse in the form of metastasis, with the tumours reproducing mainly in the liver and lung.
“When there is a diagnosis of colon cancer in the most advanced stages, oncologists do not have effective treatments at their disposal that can cure the patient,” explains
Eduard Batlle.This study paves the way for the development of the first treatment based on immunotherapy for patients with metastatic colon cancer and for those patients with poor prognosis but who have not yet developed metastasis.
“Oncologists and pharmaceutical companies will soon start clinical assays that combine TGF-beta inhibitors, which are already in clinical use, with immunotherapies. We are convinced that many colon cancer patients will benefit from this therapeutic strategy,”, they say.
Nature publishes in the same issue another study by the American pharmaceutical company Genentech that reaches the same conclusions as Batlle’s team investigating the lack of response to immunotherapy in patients with bladder cancer.
“This other work shows that the discovery goes beyond colon cancer. Apparently multiple types of tumors use the same strategy – the elevation of TGF-beta levels in the environment – to make themselves invisible to the immune system. These others could also benefit from immunotherapies based on inhibiting the action of this hormone”, say the scientists from IRB Barcelona.
The study has had the collaboration of the chemistry laboratory led by
Antoni Riera at IRB Barcelona, which has synthesized the drug that neutralizes the action of TGF-beta, and the work of
Toni Berenguer and
Camille Stephan-Otto at the head of the bioinformatics and biostatistics platform, which have validated the similarity between human and mouse tumors. The study also involved the Department of Oncology and Pathology at the Hospital del Mar de Barcelona.
The work has been carried out with grants from the BBVA Foundation, Olga Torres Foundation (FOT), Josef Steiner Foundation, the European Research Council (ERC) the Ministry of Economy and Competitiveness through FEDER funds and with the support of the Botín Foundation and Banco Santander through its Santander Universities Global Division.
Eduard Batlle and
Daniele Tauriello are also members of the CIBERONC network, Networked Biomedical Research Center in Cancer, from which the laboratory receives funds to develop its studies.
Reference article:Daniele VF Tauriello, Sergio Palomo-Ponce, Diana Stork, Antonio Berenguer-Llergo, Jordi Badia-Ramentol, Mar Iglesias, Marta Sevillano, Sales Ibiza, Adria Cañellas, Xavier Hernando-Momblona, Daniel Byrom, Joan A Matarin, Alexandre Calon, Elisa I Rivas, Angel R Nebreda, Antoni Riera, Camille Stephan-Otto Attolini and Eduard Batlle
TGF-beta drives immune evasion in genetically reconstituted colon cancer metastasis
Nature (2018). doi:
https://www.nature.com/articles/nature25492?error=cookies_not_supported&code=c6d8e5a9-4924-4944-bd3d-4955ed910ec6LINK TO THE VIDEO ANIMATION
LINK (Google Drive) to scientific
images, .
LINK (Google Drive) to scientific images, photos in the lab with the authors, press release and the summary of the article
More information Sònia Armengou. Press Office. IRB Barcelona. 93 403 72 55/618 294 070
