New Biomarker Identifies Colorectal Cancer Patients Eligible for Immunotherapy

Researchers have identified a new biomarker that may expand the number of colon and rectal cancer patients eligible for immunotherapy. Currently, only approximately 5% of patients with colon cancer are considered candidates for these treatments, largely due to the difficulty in identifying individuals likely to derive clinical benefit.

The study, published in the journal Gut, was led by a multidisciplinary team including the Hospital del Mar Research Institute (HMRIB), the Institute for Research in Biomedicine (IRB Barcelona), and the CIBER Oncology area (CIBERONC). The team identified a specific protein called collagen triple helix repeat containing 1, or CTHRC1, which serves as a prognostic and predictive biomarker.

Understanding CTHRC1(+) CAFs

The biomarker is not found in the tumor cells themselves, but in non-tumor cells within the cancer microenvironment. Specifically, the protein is expressed by a population of cancer-associated fibroblasts, known as CTHRC1(+) CAFs.

These fibroblasts are connective tissue cells that form part of the tumor microenvironment and assist in tumor proliferation. By detecting this protein in the stromal cells, clinicians may better establish a prognosis for patients and determine who might benefit from immunotherapy or treatments designed to inhibit the protein linked to tumor growth.

According to the investigators, this marker captures the activity of transforming growth factor beta (TGF-beta) within the tumor microenvironment. This specific pathway is associated with poorer patient outcomes, and high levels of the CTHRC1 protein have been linked to treatment resistance.

Validation and Clinical Application

To ensure the biomarker’s clinical utility, the research team implemented a multidisciplinary validation process using immunohistochemistry tests, which are routinely used in pathology services for colorectal tumors.

The validation process involved several stages:

• The potential of CTHRC1(+) CAFs as predictive markers was studied across 17 cohorts, which included samples from nearly 3,000 patients.
• Tumor cell RNA was analyzed at a single-cell level to identify the most promising cell populations.
• The proteins expressed by these cells were determined, concluding that only those expressing CTHRC1 retained predictive capacity.

These results were further validated using patient samples from various national and international hospitals, including the Hospital Universitario Germans Trias i Pujol, the Hospital Clínico Universitario de Valencia, and Hospital del Mar.

Impact on Personalized Treatment

Traditional biomarkers for immunotherapy eligibility typically focus on mismatch repair deficiency and microsatellite instability. This approach delineates a very small subset of patients who can benefit from immune checkpoint blockade, restricting the reach of the therapy despite its potential efficacy.

The discovery of CTHRC1 allows for a more nuanced evaluation of the immune microenvironment and tumor biology. Notably, the presence of CTHRC1(+) CAFs enables an assessment of the state of immune cells within the tumor and their ability to act against neoplastic cells.

The researchers noted that the usefulness of this marker is not limited to patients who were previously considered eligible for immunotherapy, suggesting that a larger subset of the patient population could potentially transition to these viable treatment options.