Multiverse of immune microenvironment in metastatic colorectal cancer.

The comprehensive analysis of patients with a complete resection of all metastases reveals the heterogeneity of the colorectal metastatic disease and its clinical impact. Complex tumor immune interrelations shape the metastatic landscape, not only in terms of number and size of lesions, or mutational pattern, but also in terms of immune cell infiltrate. Significantly higher densities of T-cells and lower density of B-cells were quantified in the tumor microenvironment of metastases compared with primary tumors. A high T cell infiltration and Immunoscore measured in the least-infiltrated metastasis were associated with a significantly lower number of metastases, larger metastasis, and prolonged survival while patients with increased metastatic burden had a lower Immunoscore. Immunoscore was evaluated on a biopsy, in a random metastasis or as the mean value of all metastases significantly predicting outcome. However, the most immune-infiltrated metastasis was not significantly predicting outcome, whereas the least immune-infiltrated metastasis was best in predicting clinical outcome. A good likelihood of concordance of Immunoscore was observed between one biopsy and complete metastasis, but the overall intra-metastatic immune infiltrate might be better estimated with multiple biopsies or sampling of larger tumor areas. This intra-metastatic adaptive immune reaction increases following aneoadjuvant treatment containing anti-EGFR monoclonal antibody, an effect that is currently therapeutically evaluated in clinical trials to improve the survival of metastatic patients.