Tumor‐Infiltrating Immune Cells Are More Abundant in Lung Metastases From Colorectal Cancer Than in Paired Primary Tumors and Their Prognostic Value Depends on Adjuvant Chemotherapy

ABSTRACT Introduction The immune microenvironment plays a crucial role in the progression of colorectal cancer (CRC), but its variation across primary tumors and metastatic sites remains incompletely understood. In this study, we compared the composition and prognostic significance of the immune microenvironment in lung metastases, paired primary tumors, and liver metastases from a retrospective cohort of 216 patients with metastatic CRC who underwent pulmonary metastasectomy in a single Swedish institution. Methods Immunohistochemistry was applied on tissue microarrays to evaluate CD3 + , CD8 + , CD20 + , FoxP3 + immune cells, PD‐L1 + immune cells and tumor cells, and tertiary lymphoid‐like structures (TLLS). Results Lung metastases exhibited significantly higher infiltration of all immune cell subsets compared to both primary tumors and liver metastases. FoxP3 + cell density was lower in liver metastases than in primary tumors. Immune cell infiltration in lung metastases was largely unaffected by neoadjuvant chemotherapy, except for lower FoxP3 + cell infiltration in treated cases. None of the immune markers bore prognostic significance in the overall analysis. However, high infiltration of FoxP3 + , CD20 + , and PD‐L1 + immune cells, and presence of TLLSs in lung metastases were associated with improved overall survival in patients receiving adjuvant chemotherapy, with a significant prognostic treatment interaction. None of the immune markers were prognostic in primary tumors or liver metastases. Conclusion These findings underscore a distinct, more immunologically active immune microenvironment in CRC lung metastases compared to primary tumors and liver metastases, that suggestedly also predicts response to adjuvant chemotherapy. Immune profiling of lung metastases may thus pave the way for improved personalized treatment of these patients.