They reveal how colorectal metastases block the immune system

BarcelonaThe most aggressive colorectal tumors have learned to evade the immune system and go undetected by its defenses. Although immunotherapies have revolutionized the fight against many types of cancer, colorectal cancer is still one of the leading causes of death worldwide. In most metastatic cases, patients do not respond to these drugs because their immune system does not recognize the malignant cells as a threat. But there is hopeful news. A study led by the Institute for Research in Biomedicine (IRB Barcelona) and the National Center for Genomic Analysis (CNAG) has discovered how these tumors manage to block the immune system and, therefore, limit the effectiveness of immunotherapy, the treatment that reactivates the body's defense cells to attack. The key: the hormone TGF-β. The researchers have found that, through a hormone known as TGF-β, colorectal tumors generate a double barrier that protects them from immune attack. "The issue is that the tumor microenvironment of more metastatic colon cancers is different from that of more benign ones and is characterized by the presence of TGF-β, an immunosuppressive hormone," Dr. Eduard Batlle, ICREA researcher and head of the colorectal cancer laboratory at IRB Barcelona, explained to ARA. "Malignant cells use this hormone to evade detection by T lymphocytes, the cells on which our immune system is based," he clarified.

The study, published this Friday in Nature GeneticsThis research has demonstrated how TGF-β acts as a "no entry" signal. In fact, it blocks the ability of lymphocytes to recognize the tumor and their ability to migrate into the bloodstream, while simultaneously modifying macrophages—cells that indicate the location of tumors—to produce osteopontin, the protein that inhibits the multiplication of the few T cells that manage to enter the bloodstream. Thus, immune cells cannot expand and divide within the tumor to reduce the cancer, explains Batlle. In other words, the tumor becomes virtually invisible to the immune system.

New combination therapies

Clinical trials with TGF-β inhibitors are already underway, but their use in patients is still limited due to the rather severe cardiotoxic effects they can cause. This is because the inhibitors act systemically and block this hormone throughout the body.

The study, also led by Dr. Alejandro Prados of IRB Barcelona and CIBERONC, along with Dr. Holger Heyn of CNAG, opens the door to designing combination therapies that will allow immunotherapy to be effective in more patients. One of the proposed strategies is to block the mechanisms activated by TGF-β, such as osteopontin production.

"We have collaborated with a US company that is developing antibodies that do not inhibit all TGF-β in our body, but only that of immune system cells, lymphocytes, thus avoiding the most toxic effects," adds Batlle. According to preliminary data, approximately 20% of patients show antitumor responses, some of them "substantial strength," in a phase 2 clinical trial. However, researchers caution that the complexity of these findings means they cannot yet be directly applied to patients. Further trials and research will be necessary, but the results represent a step forward in understanding metastatic colorectal cancer. The ultimate goal is for the immunotherapies These treatments could benefit the majority of people with metastatic colorectal cancer, whereas currently they only work for a small group. The goal is to find new treatments that improve patients' quality of life and increase the number of people with cancer who are cured or, at least, manage to live with the disease as a chronic condition.