Metastatic dissemination remains the leading cause of cancer-related mortality, and the mechanisms governing it remain largely unclear. Tumors develop within a complex microenvironment that comprises fibroblasts, blood vessels, lymphatic vessels, and numerous immune cell populations. To clarify the determinants of this process, the authors analyzed the tumor microenvironment at every stage of the metastatic cascade: early metastatic dissemination, synchronous metastases, and metachronous metastases. They sought to address three questions: which genes in the primary tumor influence the occurrence of distant metastases; which factors related to blood and lymphatic vascularization and to the immune response are associated with it; and whether distant metastasis is a cause or a consequence of the alteration of these factors.
The study relies on three large independent cohorts of patients with colorectal cancer, totaling 570 patients. Notably, the analysis of tumor gene expression and chromosomal instability revealed no overexpressed or amplified factor involved in tumor spread: each tumor displayed its own profile of amplifications, deletions, and expression, and no mutation in cancer-associated genes or pathways was linked to M stage. Conversely, FBXW7 mutations were associated with the absence of metastasis and correlated with increased expression of genes involved in antigen presentation and lymphocyte proliferation. Tumors lacking signs of early metastatic invasion—vascular emboli, lymphatic and perineural invasion, grouped under the acronym VELIPI—instead showed high infiltration by Th1-type T cells and memory T cells, a high Immunoscore, and a favorable outcome.
A cytotoxic immune signature, the Immunoscore, and an increased density of lymphatic vessels at the invasive margin of the tumor protected against the formation of distant metastases, independently of genomic instability. These data indicate that distant metastasis is more a consequence than a cause of the reduction in lymphatic vessels and lymphocyte cytotoxicity. The metastatic landscape proved highly heterogeneous, with each metastasis from a given patient carrying distinct tumor clones and immune microenvironments. The Immunoscore of a randomly sampled metastasis predicted major differences in survival, with the Immunoscore of the least infiltrated metastasis being most strongly associated with long-term survival.
Based on these observations, the authors propose an alternative model of tumor evolution, termed parallel immune selection, linked to the intrametastatic immune microenvironment through the process of immunoediting. During progression, immunoedited clones are eliminated while immunoprivileged clones persist and progress, highlighting the links between clonal seeding and immune surveillance. Strong intratumoral immune infiltration and a high Immunoscore prevent metastatic invasion at all its stages and are accompanied by prolonged survival.