• Lynch Syndrome (LS) is a hereditary condition involving mutations in DNA mismatch repair genes
• Researchers sequenced T cell receptors in blood and tissue samples from LS carriers and non-carriers and characterised their T cell profiles
• Study revealed unique early immune signatures in patients with LS, independent of cancer history
• Blood test could serve as non-invasive tool for early cancer detection and monitoring of immune response to cancer

Researchers at The University of Texas MD Anderson Cancer Centre have discovered a new blood-based biomarker that can help identify and characterise asymptomatic people with Lynch Syndrome (LS) who are more susceptible to developing cancer based on early immune detection signatures, allowing clinicians to stratify patients based on their personal risk level.

The study, published in Nature Communications, was led by Eduardo Vilar-Sanchez, M.D., Ph.D., chair ad interim of Clinical Cancer Prevention.

The results advance our understanding of T cell responses in LS carriers, providing personalised insights for early cancer detection, monitoring and therapeutic interventions for these individuals.

“Providing a potential non-invasive blood test to track cancer risk and immune activity in patients with Lynch Syndrome is a tremendous step forward for this patient population,” Vilar-Sanchez said.

“These are valuable insights into immune responses that can help personalise the way we monitor and direct prevention strategies.”

What is Lynch Syndrome and why did the researchers examine blood samples?

Lynch Syndrome is a hereditary condition involving mutations in the germline of DNA mismatch repair genes.

People with LS have a genetic predisposition to develop cancers with microsatellite instability, especially colorectal and endometrial cancer, and they often develop cancers at a younger age than the general population.

Having a way to understand an individual’s level of risk for developing cancer could help clinicians offer appropriate surveillance and intervention to improve outcomes.

These microsatellite mutations, which result in insertions or deletions of DNA sequences, also create tumour-specific neoantigens.

These neoantigens are protein fragments on cancer cells that T cells recognise as foreign, triggering an immune response.

The researchers sequenced T cell receptors (TCR), which help T cells identify and attack threatening neoantigens on cancer cells.

They characterised the TCRs found in peripheral blood mononuclear call (PBMC) samples – which contain crucial T cells involved in immune defence – from 277 people, including 102 survivors of LS, 130 carriers without a history of cancer (previvors), and 45 controls without LS or cancer.

They also performed TCR sequencing in the colorectal tissues of three cancers and 11 pre-cancers matched to those PBMC samples.

What did the blood and tissue samples show?

In colon tumours and pre-cancer tissues, certain T cells – identified by their corresponding TCRs – were expanded in response to these tumour-specific neoantigens.

Up to 41% of the expanded TCRs from colon pre-cancers and tumours were detected in LS carriers but not in people without LS, suggesting that the immune system is surveilling and responding to early signs of cancer.

The researchers then used this data to generate a classification model that distinguishes LS carriers from control samples simply by looking at the TCR patterns in blood.

This model helped identify LS carriers, independent of cancer history, along with cancer-free LS previvors.

What are the implications of this study?

The study found that circulating cancer-associated TCRs can be identified in blood samples from LS carriers, providing unique immune signatures that could detect individuals at higher risk of cancer development.

While further validation is needed, this blood-based biomarker could serve as a non-invasive tool for early detection, risk assessment and personalised surveillance for patients with LS.

Source: University of Texas M. D. Anderson Cancer Center