The treatment of metastatic colorectal cancer relies on the assumption that metastases within a given patient are homogeneous. However, more than 90% of patients with synchronous metastases die within five years of diagnosis, underscoring the need for a better understanding of the metastatic process. This process cannot be explained solely by the genomic alterations of tumor cells: the microenvironment in which these cells become established also plays a decisive role. Within this framework, the authors set out to map the diversity of immune infiltrates within colorectal metastases and to assess its clinical significance.
The researchers quantified immune cell types across 603 whole slides of metastases and primary colorectal tumors, obtained from 222 patients who had undergone complete resection of all their metastases. Quantification was based on automated immunohistochemistry targeting numerous markers (CD3, CD8, CD45RO, CD20, FOXP3, CD68, PD1, PD-L1, among others), with digital measurement of cell densities in the tumor core and the invasive margin in order to calculate the Immunoscore (scale of 0 to 4). Mutational diversity was explored using a panel of 50 oncogenes or tumor suppressor genes, and RAS, BRAF, and microsatellite instability statuses were determined for all patients. The mean follow-up duration reached 44.5 months.
The analyses reveal marked heterogeneity, both between patients and between the different lesions of a given patient: primary tumors, as well as synchronous and metachronous metastases, display varied immune infiltrates and mutational profiles. Small metastases frequently exhibited a low Immunoscore and low T- and B-cell scores, whereas a high Immunoscore was associated with a reduced number of metastases. Treatment with anti–epidermal growth factor receptor (anti-EGFR) therapy altered immune gene expression and significantly increased T-cell density at the core of metastases. Moreover, the predictive accuracy of the Immunoscore assessed on a single biopsy proved superior to that of PD-L1 staining.
The most striking clinical finding lies in the fact that the immune phenotype of the least infiltrated metastasis shows a stronger association with patient outcome than the other metastases. Adaptive immune cells and the Immunoscore measured in this least infiltrated lesion thus constitute the parameters most strongly linked to long-term survival, highlighting the importance of taking intermetastatic heterogeneity into account in the prognostic assessment of metastatic colorectal cancer.