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Therapeutic Implications of the Immunoscore in Patients with Colorectal Cancer

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Beyond the TNM-staging system, biomarkers are needed to guide cancer treatments. We provide an overview of the Immunoscore, a standardized immune assay based on quantification by digital pathology of CD3+ and CD8+ cytotoxic T cells in tumor tissues. We discuss the usefulness of the Immunoscore (IS) and biopsies-adapted IS (ISB) biomarkers for prediction of clinical outcome and treatment response in colonic and rectal cancers.

Abstract

Four decades were needed to progress from the first demonstration of the independent prognostic value of lymphocytes infiltration in rectal cancers to the first recommendation from the international guidelines for the use of a standardized immune assay, namely the “Immunoscore” (IS), to accurately prognosticate colon cancers beyond the TNM-system. The standardization process included not only the IS conceptualization, development, fine-tuning, and validation by a large international consortium, but also a demonstration of the robustness and reproducibility across the world and testing of international norms and their effects on the IS. This is the first step of a major change of paradigm that now perceives cancer as the result of contradicting driving forces, i.e., the tumor expansion and the immune response, interacting dynamically and influencing the prognosis and the response to therapies. This prompted us to evaluate and evidence the capacity of the tumor immune status, as reflected by the IS, to accurately predict chemotherapy responses in an international, randomized cohort study of colon cancer. Moreover, we developed a derived IS performed on initial diagnostic biopsies (ISB) to assess response levels to neoadjuvant therapies. In rectal cancer, ISB was positively correlated with the degree of histologic response to neoadjuvant chemoradiotherapy and identified - alone and even more accurately if combined with clinical data- patients eligible for a noninvasive strategy. Based on these results, we are currently setting up an international cohort for confirmation. The potential role of IS with immunotherapies must be anticipated.

SUBMITTER: El Sissy C

PROVIDER: S-EPMC8001764 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Colorectal cancer (CRC) is a leading cause of cancer incidence and mortality in the United States. Notwithstanding major improvements in the early detection and treatment of CRC, an important proportion of patients who received a diagnosis of localized disease ultimately have a recurrence and die, underscoring the need of new therapeutic approaches. Vitamin D and physical activity (PA) have emerged as 2 potential interventions for both prevention and treatment of CRC. Plausible biological mechanisms have been described for the antineoplastic effects of vitamin D and PA, and a wealth of epidemiological evidence indicates that 25(OH)D (the main circulating form of vitamin D) and PA levels are inversely associated with CRC risk. Recent efforts have now focused on the role of vitamin D and PA as adjunct treatments after a CRC diagnosis. Observational studies evaluating prediagnosis and postdiagnosis circulating 25(OH)D levels among patients with CRC of all stages have found that subjects with levels in the highest quantiles have improved overall and CRC-specific survival compared with those with levels in the lowest quantiles. Similarly, prospective studies of PA have found that higher levels of postdiagnosis PA are associated with lower overall and CRC-specific mortality in patients with nonmetastatic CRC. Meta-analyses of the observational studies of 25(OH)D and postdiagnosis PA have confirmed significant protective associations against overall and CRC-specific mortality, as well as significant dose-response relationships. No randomized controlled trial of vitamin D or PA using survival outcomes as endpoints has been completed to date. Two randomized, placebo-controlled trials of vitamin D in patients with metastatic CRC assessing patient survival as an endpoint are underway: the first is a phase II trial comparing high-dose vitamin D3 (8000 IU/d for 2 weeks followed by 4000 IU/d) versus standard dose (400 IU/d), and the second is a phase I-II trial comparing customized oral doses of vitamin D3 titrated to raise serum 25(OH)D levels to 80 to 100 ng/mL versus 2000 IU/d. For PA, the ongoing phase III CHALLENGE (Colon Health and Life-Long Exercise Change) study is the first randomized controlled trial using survival as an endpoint among patients with stage II-III colon cancer. The results of these trials will pave the way to more conclusive phase III trials that will provide more definitive answers about the role of these interventions in the treatment of CRC. Lastly, the advent of genomic technologies will allow identifying molecular signatures in CRC associated with improved response to vitamin D and PA and will usher in a precision medicine approach to these therapies.

Project description:ObjectivesThe Immunoscore can categorize patients into high- and low-risk groups for prognostication in colorectal cancer (CRC). Collagen plays an important role in immunomodulatory functions in the tumor microenvironment (TME). However, the correlation between collagen and the Immunoscore in the TME is unclear. This study aimed to construct a collagen signature to illuminate the relationship between collagen structure and Immunoscore.MethodsA total of 327 consecutive patients with stage I-III stage CRC were included in a training cohort. The fully quantitative collagen features were extracted at the tumor center and invasive margin of the specimens using multiphoton imaging. LASSO regression was applied to construct the collagen signature. The association of the collagen signature with Immunoscore was assessed. A collagen nomogram was developed by incorporating the collagen signature and clinicopathological predictors after multivariable logistic regression. The performance of the collagen nomogram was evaluated via calibration, discrimination, and clinical usefulness and then tested in an independent validation cohort. The prognostic values of the collagen nomogram were assessed using Cox regression and the Kaplan-Meier method.ResultsThe collagen signature was constructed based on 16 collagen features, which included 6 collagen features from the tumor center and 10 collagen features from the invasive margin. Patients with a high collagen signature were more likely to show a low Immunoscore (Lo IS) in both cohorts (P<0.001). A collagen nomogram integrating the collagen signature and clinicopathological predictors was developed. The collagen nomogram yielded satisfactory discrimination and calibration, with an AUC of 0.925 (95% CI: 0.895-0.956) in the training cohort and 0.911 (95% CI: 0.872-0.949) in the validation cohort. Decision curve analysis confirmed that the collagen nomogram was clinically useful. Furthermore, the collagen nomogram-predicted subgroup was significantly associated with prognosis. Moreover, patients with a low-probability Lo IS, rather than a high-probability Lo IS, could benefit from chemotherapy in high-risk stage II and stage III CRC patients.ConclusionsThe collagen signature is significantly associated with the Immunoscore in the TME, and the collagen nomogram has the potential to individualize the prediction of the Immunoscore and identify CRC patients who could benefit from adjuvant chemotherapy.

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Therapeutic Implications of the Immunoscore in Patients with Colorectal Cancer

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