UK Researchers ID Mechanism Cancer Cells Use to Hide from the Immune System

colon cancer cells under microscope

The field of immuno-oncology—revving up the immune system to attack cancer cells while simultaneously inhibiting cancer cells’ ability to hide from the immune system—seems almost miraculous. But research is being conducted daily that is finding out even more of cancer’s secrets. This week, a researcher with The Institute of Cancer Research (ICR), London, and the Royal Marsden NHS Foundation Trust published research that showed another mechanism for how colon cancer cells hide from the immune system. They published their work in the Journal of ImmunoTherapy of Cancer.

“Cancer is very good at hiding from the body’s immune system,” stated Marco Gerlinger, Team Leader in Translational Oncogenomics at the ICR. “The latest successful immunotherapies work by acting as a matchmaker to bring the immune system together with cancer, so that it can see it and attack it.”

Gerlinger added, “Our study has found that bowel cancers have a way of dodging even the newest of immunotherapies—changing their spots by altering the levels of a key molecule on the surface of cells, so that they become harder to recognize.”

Colorectal cancer (CRC) is the third most common cause of cancer-related death globally. New therapies are good at extending cancer patients’ life, but there’s room for improvement. Immuno-oncology treatments, especially checkpoint inhibitors, have been only effective in some CRC patients with hypermutated microsatellite instability (MSK). Checkpoint inhibitors haven’t been very effective against most types of CRC, including microsatellite stable (MSS) CRC.

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The researchers developed patient derived colorectal cancer organoids (PDOs), which basically means they grew mini-tumors to use as models for a variety of cancer drugs. They established the PDOs from multidrug-resistant metastatic CRCs.

One of the promising new immunotherapy drugs is cibisatamab, being developed by Roche. One arm of the drug attaches to CEA, which is on the surface of several types of cancer cells and is the primary marker for bowel cancer. Another arm of the drug activates T-cells, which then attack the tumor.

One of their findings was that many of these organoids, or mini bowel cancers, could hide from treatment. They did so by shifting from high to low levels of a molecule called carcinoembryonic antigen (CEA).

The team book biopsies from eight bowel cancer patients. They then used a new technique to grow the organoids of the tumors. They identified three groups of cells, some with high levels of CEA on the cancer cells’ surface, some with low levels, and some with a mixture.

They found that treatment with cibisatamab reduced growth by 96% in cancer cells with high CEA levels, but only by 20% in the cancer cells with low CEA. In the cancer cells with mixed levels of CEA, the drug decreased growth by 53%.

The researchers then isolated the individual cells with high or low CEA and regrew them into organoids. What they found was that the CEA levels changed in the regrown tumors. This suggests that the cancer cells can quickly shift to a different state and they use this to “hide” from immunotherapy.

They then analyzed the active genes in the organoids and found that the cancer cells with low levels of CEA had increased activity in what is called the WNT pathway of genes. This pathway is targeted by several drugs currently in development.

The researchers found that treating the bowel cancer organoids with tankyrase inhibitors and porcupine inhibitors, drugs that target the WNT pathway and increase CEA levels, made the cancer more vulnerable to immunotherapy.

The results of this research has the possibility of revolutionizing immunotherapy treatment for colorectal cancer.

“As we move away from one-size-fits-all therapy for cancer, it’s so important that we are able to identify which patients are most likely to respond to a drug, and do everything we can to avoid resistance to treatment for as long as possible,” stated Paul Workman, Chief Executive of the ICR. “This research reveals a way in which cancers are able to hide from a promising new type of immunotherapy. Although the work is still in its early stages, it could be used to develop a test for who is most likely to respond to the drug, and points to possible drug combinations that might prevent or delay resistance.”

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