NSCLC patients with oligo-metastatic brain disease show an altered CD4 T-cells immune profile

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Abstract Background Lung cancer is the leading cause of cancer-related deaths worldwide, with brain metastasis (BM) occurring in 40% of advanced non-small cell lung cancer (NSCLC) patients. In 15% of these patients, the brain is the only affected organ (oligo-metastasis), corresponding to improved prognosis compared to widespread disease. Thus far, it is unknown if the metastatic dissemination to the brain without systemic metastases is a consequence of the immune system’s ability to control systemic tumor outgrowth. Methods Here, we investigated the local and peripheral immune cell composition in NSCLC BM patients, and identified new immune patterns related to the occurrence of brain metastases either as oligo- or poly-metastatic disease. Results The multi-parametric immune phenotyping of peripheral blood revealed a downregulation of KLRG1 in CD8 + T-cells and an increase in CD4 + T H 17 cells and elevated IL-17 levels in the blood of all NSCLC BM patients compared to healthy individuals. In addition, BM patients CD4 + T cells showed less CD73 expression with reduced effector memory differentiation. Furthermore, we observed less intra-tumoral infiltration in tumor tissues and a distinctive CD4+ T-cell profile in oligo-synchronous BM, both in the tumor microenvironment and peripheral blood compared to poly-metastatic BM patients. Moreover, 5′-ectonucleotidase CD73 was significantly upregulated in CD4 and T-regulatory cells of oligo-synchronous BM. Conclusions These results indicate that oligo-synchronous BM exhibits a more pronounced alteration in the CD4 T-cell immune profile both locally at the tumor site and systemically. Key Points BM patients exhibit a skewed systemic immune profile, characterized by downregulation of KLRG1 in CD8 + and induction of T H 17/IL-17 axis and CD73 in CD4 + T-cells. Oligo-synchronous BM displayed a distinct CD4 + T-cell profile in both TME and peripheral blood. Importance of the Study This study presents a novel insight into immune profiles of brain metastasis types in NSCLC patients. Examining tissues and PBMCs sheds light on the disease and uncovers unique immune responses within distinct brain metastasis patterns. This research offers valuable knowledge for improved understanding and identifying potential prognosis markers.

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