Abstract Non-small cell lung cancer (NSCLC) contains a highly diverse immune landscape, making it challenging to identify markers that truly reflect how the tumor interacts with the immune system. Recent research has identified CCR8 as a key marker for a particularly suppressive group of regulatory T cells (Tregs) that accumulate within tumors. In this study, we aimed to investigate the impact of CCR8+ Tregs on disease outcomes in NSCLC and to deepen our understanding of their role in facilitating tumor evasion of the immune response. We employed various techniques, including multiparametric flow cytometry, RNA sequencing, and spatial immunohistochemistry, using NSCLC cell lines (H1299 and H1573) and patient-derived tumor samples to assess their effects. We observed that CCR8+ Tregs were significantly enriched within tumor tissue compared to adjacent normal lung tissue. These CCR8+ Tregs expressed higher levels of potent immunosuppressive molecules, including CTLA-4, TIGIT, and IL-10, as well as genes associated with TGF-β signaling, distinguishing them from CCR8- Tregs. Tumors with a high density of CCR8+ Tregs had fewer CD8+ T cells, reduced effector cytokine production, and lower levels of granzyme B, indicating weakened antitumor immunity. Additionally, patients with elevated CCR8+ Treg infiltration tended to have more advanced diseases and shorter progression-free and overall survival, even after adjusting for standard clinical factors. Statistical modeling confirmed that CCR8+ Treg levels independently predict patient outcomes. Further analysis and in vitro assays using NSCLC cell lines revealed that CCL1-CCR8 interactions likely drive the recruitment and retention of these cells within tumors. Overall, our findings show that CCR8+ Tregs represent a uniquely suppressive immune population and a strong prognostic marker in NSCLC, supporting the development of therapies that specifically target CCR8 to enhance antitumor immunity. Citation Format: Santosh K. Singh, Manoj K. Mishra, Eric Flenaugh, Gabriella M. Oprea-Ilies, Brian M. Rivers, James W. Lillard, Shailesh Singh, Rajesh Singh. CCR8+ regulatory T cells represent a promising prognostic marker for non-small cell lung cancer (NSCLC) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5369.
Singh et al. (2026) studied this question.