How colorectal cancer escapes from the immune system early on

An international study co-led by scientists from Human Technopole reveals that colorectal tumours use both genetic and epigenetic strategies to evade immune detection almost immediately after they transform into cancerous. The results, published in Nature Genetics, challenge previous notions that immune evasion occurs gradually over time.

Colorectal cancer is the third most common cancer worldwide. Despite advances in screening and treatment, it remains a leading cause of cancer-related death. A key reason is its ability to escape detection and destruction by the immune system. Although it has long been known that tumours can evolve to evade immune responses, the timing and mechanism of this process remains unclear.

To address this question, researchers from Human Technopole (Italy), The Institute of Cancer Research London (United Kingdom), and Chalmers University of Technology (Sweden) analysed nearly 500 tumour samples from 29 colorectal cancer patients.  Using advanced genomic, transcriptomic, epigenetic and imaging profiling, they examined individual tumour glands to pinpoint when and where immune evasion occurs.

They found that many tumours lose the ability to effectively present neoantigens, molecular flags that help the immune system to identify and attack cancer cells. Importantly, they observed that this loss was not driven by genetic mutations, but by epigenetic changes, i.e. alterations in how DNA is packaged and read. These epigenetic modifications silenced genes responsible for immune signaling and antigen presentation, effectively allowing cancer cells to hide from immune attack.

The researchers also found that these changes were clonal, meaning they occurred early and were shared by all parts of the tumour. This pattern, described as a “Big Bang” model of immune escape, suggests that once these immune-evasive features are in place, they shape the entire course of cancer development.

These findings have important implications for cancer research and treatment. Immunotherapies, such as immune checkpoint inhibitors, rely on the immune system recognising and attacking tumours. However, if tumours have already disabled these recognition pathways early on, such therapies may be ineffective, thus explaining why some colorectal cancers fail to respond to current treatments.

By highlighting the role of epigenetic silencing in immune escape, the study points to potentially new therapeutic targets. Drugs that reactivate silenced genes or prevent their shutdown could make tumours more visible to the immune system and enhance the success of immunotherapies. Therefore, these results may pave the way for early detection, patient stratification, and combination treatments involving both immunotherapy and epigenetic drugs.