The Immunoscore predicts patient outcomes more accurately than standard TNM staging and could help guide treatment choices, such as using stronger adjuvant chemotherapy for high-IS stage III microsatellite stable (MSS) colorectal cancer or identifying proficient MMR (pMMR/MSS) metastatic colorectal cancer patients who may respond to immune checkpoint inhibitors.
Those are key take-home messages from an invited commentary in The Journal of Pathology: Clinical Research by Matthew Hsu, MBBS, and Suet Yi Leung, MBBS, MD, of the department of pathology in the School of Clinical Medicine at The University of Hong Kong.
According to the authors, routine colorectal cancer (CRC) pathology focuses on TNM staging, mismatch repair (MMR) status, and key molecular alterations. While these tools remain essential, they do not fully explain why patients with similar tumors often have markedly different outcomes. A growing body of evidence, they say, points to the local immune response as a critical missing piece.
The Immunoscore is a standardized pathology-based assay that quantifies CD3+ and CD8+ T-cell densities in two tumor regions: the tumor core and the invasive margin. These measurements are combined into a single score that reflects the strength of the antitumor immune response. As noted by the authors, large international validation studies involving more than 3,000 patients consistently show that Immunoscore provides superior prediction of recurrence and survival compared with TNM staging or MMR status alone.
For gastroenterologists, the most clinically relevant data involve stage III colon cancer. According to the commentary, multiple international cohort studies demonstrate that patients with a high Immunoscore experience significantly improved disease-free and overall survival when treated with adjuvant chemotherapy. On the other hand, patients with a low Immunoscore have similar outcomes whether they receive chemotherapy or not. Given that only a minority of stage III patients derive meaningful benefit from adjuvant treatment, Immunoscore may help identify those most likely to benefit as well as those who may be overtreated.
Immunoscore also refines risk stratification beyond MMR status. As noted in the commentary, although MSI-high tumors are generally associated with a favorable prognosis, Immunoscore identifies a high-risk subgroup within MSI-high disease. The authors report that patients with low Immunoscore have significantly higher recurrence rates than those with high Immunoscore. The commentary further highlights that, among MSS tumors, a high Immunoscore identifies patients with better-than-expected outcomes. Taken together, the authors conclude that Immunoscore more directly captures underlying immune biology than MSI testing, which functions primarily as a surrogate marker of immune infiltration.
The commentary highlights emerging data on Immunoscore-IC, an expanded version that incorporates PD-L1–positive cell density and spatial relationships between immune cells. In the AtezoTRIBE trial, Immunoscore-IC identified a substantial subset of patients with metastatic, proficient-MMR CRC who benefited from adding atezolizumab to first-line chemotherapy. According to the authors, this is notable, as most MSS CRCs do not respond to immune checkpoint inhibitors using conventional biomarkers.
The authors note that despite a strong evidence base, Immunoscore has not been widely implemented in routine clinical practice. They note several barriers, including dependence on proprietary digital pathology platforms, cost, technical complexity, and the need for standardized training. In addition, much of the supporting evidence comes from studies that looked back at existing data, and the current test measures only certain types of immune cells rather than the full immune response.
Still, the authors maintain that Immunoscore represents an important step toward immune-informed staging and treatment selection in CRC. “Integration into routine clinical practice and international guidelines could optimize patient stratification,” they wrote. “Prospective validation in different tumor types beyond CRC, and combination with complementary biomarkers will be crucial next steps.”
This work was supported by the Centre for Oncology and Immunology under the Health@InnoHK Initiative funded by the Innovation and Technology Commission, The Government of Hong Kong SAR, China.