Metastatic colorectal cancer continues to carry a poor prognosis: more than 90% of patients with synchronous metastases die within five years of diagnosis. A better understanding of the determinants of metastatic progression therefore represents a major challenge. Beyond the genomic alterations of tumor cells, it is the immune microenvironment that shapes the fate of secondary lesions. To investigate this dimension, the authors drew on a comprehensive analysis of 222 stage IV patients who underwent complete curative resection of all their metastases, amounting to 603 lesions in total, quantified by automated whole-slide reading in order to map the spatial distribution of lymphocytes (notably CD3+, CD8+, CD45RO+, CD20+, and FOXP3+) within the tumor core and the invasive margin.
As with primary tumors, metastases display a non-uniform immune infiltration, generally denser at the invasive margin. Compared with primary tumors, they contain significantly more T lymphocytes and fewer B lymphocytes. The most striking feature in patients with multiple lesions is the heterogeneity between metastases, both in lymphocytic infiltrate and in somatic mutation profile. A high T-lymphocyte infiltration and a high Immunoscore, measured in the least infiltrated metastasis, are associated with a lower number of metastases, larger lesions, and prolonged survival, whereas an increased metastatic burden is accompanied by a lower Immunoscore (P < 0.001). Notably, it is the least infiltrated metastasis, rather than the most infiltrated one, that best predicts clinical outcome. The team also assessed the ability of a single biopsy to estimate the infiltrate. A single biopsy correctly identifies poorly infiltrated tumors in more than 90% of cases, but may over- or underestimate the infiltrate in heterogeneous tumors; sensitivity improves by increasing the number of samples or by sampling larger areas. CD3, CD8, and the Immunoscore prove to be more sensitive and specific than PD-L1 in reflecting the true state of the metastatic slide. Finally, preoperative treatment alters the immune microenvironment. The combination of chemotherapy with an anti-EGFR monoclonal antibody (cetuximab) specifically increases T-lymphocyte infiltration within the core of metastases, whereas an anti-VEGF combined with chemotherapy instead promotes the expression of B-lymphocyte and NK-cell genes. RAS mutational status does not influence the baseline Immunoscore but determines a lesser T-cell infiltration in response to anti-EGFR therapy. This adaptive intra-metastatic immune response, enhanced by neoadjuvant treatment, is currently being evaluated in several clinical trials aimed at improving the survival of metastatic patients.