Blood-Based T-Cell Receptor Signatures as a Biomarker for Cancer Risk in Lynch Syndrome

Lynch syndrome (LS) is the most common hereditary cancer predisposition syndrome. It is caused by germline mutations in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2). Individuals with Lynch syndrome face substantially increased lifetime risks for colorectal, endometrial, and other cancers, often presenting at a younger age than the general population.

The syndrome is characterized by microsatellite instability (MSI), a molecular hallmark reflecting MMR deficiency, which leads to the accumulation of mutations and the generation of tumor-specific neoantigens that can be recognized by the immune system. Risk stratification and surveillance in Lynch syndrome currently rely primarily on genetic and family history assessment, but improved non-invasive biomarkers for early cancer detection and immune monitoring are needed.

The outcomes of a recent study, led by researchers at The University of Texas MD Anderson Cancer Center and supported by institutional and extramural funding, were published in Nature Communications.[1] Based on the study results, the researchers have identified blood-based T-cell receptor (TCR) signatures that may serve as a biomarker for cancer risk and immune surveillance in individuals with Lynch syndrome. [2]

The research team, led by Eduardo Vilar-Sanchez, M.D., Ph.D., analyzed TCR repertoires in peripheral blood and matched colorectal tissue samples from Lynch syndrome carriers and controls to characterize Lynch syndrome-specific immune responses and explore the potential of blood-based TCR profiling for early cancer detection.

Study design
The study cohort comprised 277 individuals: 102 Lynch syndrome cancer survivors, 130 unaffected Lynch syndrome carriers (‘previvors’), and 45 non-Lynch syndrome controls. Peripheral blood mononuclear cells (PBMCs) were collected, and TCR sequencing was performed to profile circulating T-cell clones.

In a subset, TCR sequencing was also conducted on matched colorectal tissue samples from colorectal cancers and pre-cancerous lesions. The presence and expansion of cancer-associated TCRs in blood and tissue were analyzed, and a classification model was developed to distinguish Lynch syndrome carriers from controls based on circulating TCR patterns.

Findings

• Lynch syndrome-Specific Immune Signatures: Up to 41% of the most expanded TCRβ sequences identified in colorectal pre-cancers and cancers from Lynch syndrome carriers were also detectable in their peripheral blood. In contrast, these expanded TCRs were largely absent in controls without Lynch syndrome.
• Cancer-Independent Detection: The unique TCR signatures were found in Lynch syndrome carriers irrespective of cancer history, indicating that these immune features reflect inherited risk rather than only a response to existing tumors.
• Classification Model: Using circulating TCRβ profiles, the researchers developed a model that distinguished Lynch syndrome carriers—including cancer-free carriers—from non-Lynch syndrome controls.
• Non-Invasive Biomarker Potential: These findings support the use of blood-based TCR sequencing as a non-invasive approach for risk assessment, early detection, and monitoring of immune responses in Lynch syndrome.

Clinical and Biological Implications
The Implications of the identification of Lynch syndrome-specific TCR signatures:

• Personalized Surveillance: A blood-based test could help stratify Lynch syndrome carriers by risk, enabling more tailored surveillance and intervention strategies.
• Cancer Prevention and Early Detection: Monitoring the immune repertoire could detect early immune responses to emerging neoplasms before clinical manifestation, providing a window for preventive action.
• Therapeutic Monitoring: As immunotherapy is highly effective in MSI-high tumors, TCR profiling might also inform therapeutic response and residual disease monitoring.

Lynch Syndrome and Immune Surveillance
Approximately 1 in 279 people are diagnosed with Lynch syndrome, making it more common than previously believed. The lifetime risk for colorectal cancer in Lynch syndrome carriers ranges from 40% to 80%, compared to 5% in the general population, with increased risks for endometrial, ovarian, small bowel, urinary tract, and brain cancers. Lynch syndrome is inherited in an autosomal dominant pattern, and genetic counseling is recommended for families with characteristic histories.

Microsatellite instability, resulting from deficient MMR, leads to the accumulation of mutations and neoantigens in tumors. These neoantigens are recognized by T cells, potentially leading to robust immune responses. Indeed, MSI-high cancers respond well to immune checkpoint inhibitors, and aspirin has been shown to reduce cancer risk in Lynch syndrome carriers, possibly via immune-mediated mechanisms.

Current Management and Future Directions
Lynch syndrome management includes regular colonoscopy, gynecologic surveillance, and, for some, prophylactic surgery. Immunotherapy and chemoprevention trials (e.g., aspirin, vaccines) are ongoing. The development of a blood-based TCR biomarker could further personalize surveillance and prevention.

This study demonstrates that circulating TCR signatures can identify LS carriers and may serve as a non-invasive biomarker for cancer risk and immune surveillance. Further validation is needed, but these findings represent an important advance toward personalized cancer prevention and early detection in Lynch syndrome.

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Note: * The authors thank the study participants and their families.

References
[1] Deng N, Duzagac F, Bolivar AM, Reyes-Uribe L, Taggart MW, Thirumurthi S, Ricciardiello L, Lynch PM, Nancy You Y, Kopetz S, Scheet P, Lizee GA, Reuben A, Marin F, Pineda M, Sinha KM, Bansal A, Capella G, Vilar E. Genomic analysis of T Cell receptors reveals lynch syndrome specific immune signatures. Nat Commun. 2026 Apr 3. doi: 10.1038/s41467-026-71243-z. Epub ahead of print. PMID: 41932865.
[2] The Onco’Zine Brief: Lynch Syndrome and Genetic Testing. May 24, 2022 [Audio/Broadcast]. Last accessed on April 8, 2022.

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