Altered CD4 T cell response in oligometatastic non-small cell lung cancer brain metastasis

Lung cancer is the leading cause of cancer mortality globally, with brain metastasis (BM) in 40% of advanced non-small-cell lung cancer (NSCLC) cases. In 15% of these cases, the brain is the sole affected organ (oligometastasis), which correlates with a better prognosis compared to widespread disease. It remains unclear if brain-only metastasis without systemic spread is due to the immune system's ability to control systemic tumor progression. We studied the immune cell compositions in NSCLC patients with BM, identifying novel patterns associated with BM, and specifcally with either oligo- or polymetastatic spread. Multi-parametric immune phenotyping of peripheral blood primarily showed alterations in the CD4⁺ T cell compartment, with increased CD4⁺ T_H17 cells, and higher IL-17 levels in NSCLC BM patients compared to healthy individuals. Furthermore, CD4⁺ T cells in BM patients exhibited lower CD73 expression and reduced effector memory differentiation. There was also decreased intratumoral infiltration and a distinct CD4⁺ T cell profile in oligo-synchronous BM, both in the tumor microenvironment and peripheral blood, compared to polymetastatic BM patients. Additionally, CD73 was significantly upregulated in CD4⁺ and T regulatory cells of oligo-synchronous (BM simulantously with primary-tumor diagnosis) BM. These findings suggest that CD4⁺ T cells play a crucial role in the biology of NSCLC BM and potentially contribute to differences in metastatic patterns, as oligo-synchronous BM shows a more significant alteration in the CD4⁺ T cell immune profile, both locally at the tumor site and systemically.