Metastatic dissemination remains one of the main determinants of prognosis in colorectal cancer, and the classical models of tumor evolution—driver mutation accumulation, the "big bang" model, neutral evolution, or branched evolution—have long focused solely on cancer cells. These approaches largely overlook the influence of the immune microenvironment on the trajectory of tumor clones. It is precisely this interaction that the authors sought to characterize, by analyzing how the immune context of each metastatic organ shapes clonal evolution over time.
To this end, the team assembled a longitudinal dataset of metastatic colorectal cancer, combining multiplexed analyses of gene expression, tumor clone sequencing, and immune assessment of metastatic sites. The Immunoscore, an indicator of lymphocytic infiltration, and the spatial proximity between proliferating tumor cells (Ki67+) and T lymphocytes (CD3+) were used to characterize local immune pressure. The researchers also developed an immunoediting score, based on the depletion of expected neoantigens, and verified its robustness through permutation models as well as through validation in independent cohorts of ovarian cancer and colorectal cancer.
The results show that clonal evolution patterns are closely dependent on the immune context of the metastatic site. Genetic depletion of neoantigens was observed at sites with a high Immunoscore and high spatial proximity between proliferating tumor cells and T lymphocytes. Clones that had undergone this immunoediting were eliminated and did not recur, whereas progressing clones benefited from immune privilege, persisting despite the presence of tumor-infiltrating lymphocytes. Characterization of these privileged metastases revealed escape mechanisms that were both intrinsic and extrinsic to the tumor cells. The lowest risk of recurrence was associated with the combination of a high Immunoscore, the occurrence of immunoediting, and a low tumor burden. Immunoediting proved to be the best parameter for distinguishing eliminated clones from persistent ones (AUC greater than 0.88), and its predictive value was confirmed in the validation cohorts, where the absence of immunoedited clones significantly increased the risk of metachronous recurrence.
Building on these observations, the authors propose a model of parallel selection in metastatic progression, in which the branched evolution of tumors can be traced back to clones that escaped immune surveillance. This work sheds light on the understanding of tumor dissemination and could contribute to the development of immunotherapeutic approaches.