Systemic immune remodeling following curative (R0) resection of colorectal liver metastases

Colorectal cancer liver metastases (CRLM) are a key driver of systemic immunosuppression and a determinant of poor prognosis. While surgical resection remains the mainstay of treatment, the dynamics of the immune landscape post-resection remain insufficiently characterized. This study aims to delineate immune reprogramming following liver resection in CRLM patients, offering insights into potential therapeutic strategies.

Peripheral blood samples were collected from CRLM patients before and after liver resection. Peripheral blood mononuclear cells were analyzed using multiparameter flow cytometry with adaptive and innate immunity panels, processed with FlowJo and FlowAI. Tumor immune microenvironment (TIME) was assessed by H&E, immunohistochemistry, and immunofluorescence.

Postoperative analysis revealed remodeling of T cell composition, with a significant increased proportion of CD4+ T cells among circulating CD3+ T cells, including the CD28+ CD4+ subset, while regulatory T cells and T follicular helper cells remained unchanged. Overall proportion of CD8+ T cells among circulating CD3+ T cells was reduced. Among immune checkpoint-associated populations, the percentage of TIM3+ CD4+ T cells decreased significantly, whereas PD-1+ CD4+ T cells and exhausted PD-1+ TIM3+ double-positive T-cell subsets showed modest downward trends. Innate immune populations remained largely unchanged. Patients who experienced recurrence had higher postoperative proportion of S100A9+ monocytic myeloid-derived suppressor cells (M-MDSCs). Exploratory analyses further suggested that KRAS-mutated tumors may be associated with distinct postoperative immune profiles.

Liver metastasis resection is associated with CD4+ T cell-dominant systemic immune remodeling and changes in exhaustion-associated markers, hypothetically suggesting a potential postoperative window for future immunotherapeutic interventions. Although highly speculative and requiring further functional validation, these findings suggest that the altered CD4+ T cell landscape warrants further investigation regarding its potential relevance to adoptive cellular therapies or immune checkpoint inhibition.