BACKGROUND: The lung tumor microenvironment (TME) plays a crucial role in the progression and metastasis of lung cancer. It consists of various cell types that interact in complex ways to influence tumor behavior. CD45(+) cells, as a component of the TME, have complex and multifaceted roles in lung cancer. The balance between the anti-tumor and pro-tumor functions of CD45(+) cells can significantly affect lung cancer outcomes. Understanding these roles is essential for developing targeted therapies that harness the beneficial effects of CD45(+) cells while mitigating their harmful effects. METHODS: We performed single-cell RNA sequencing of sorted CD45(+) immune cells from healthy lungs, orthotopic LLC1 tumors, and Kras(LA2) (Kras) genetically engineered tumors. Analyses included immune composition, transcriptional programs, differentiation trajectories, metabolic states, and ligand-receptor-based intercellular communication networks. RESULTS: Four major immune compartments, B cells, T cells, NK cells, and macrophages, underwent model-specific remodeling. LLC1 tumors showed B cell expansion and T and NK cell reduction, with inflammatory, stress-response, and NF-kappaB/TNF-dominant programs. Kras(LA2) tumors retained a balanced immune composition but exhibited metabolic rewiring, elevated antigen-presentation signatures, and selective intercellular signaling. Subclustering revealed specialized changes across B cell (resting, mature, pre-Bcr, late pro-B, plasma), T cell (Cd4(+), Cd8(+), memory, activated, Treg, Th17), NK cell (Fcgr3(high), Fcgr3(low), Xcl1(+)), and macrophage (Ace(+), Bcr(+), Ccr2(+), Cd3(+), metabolic, MHCII(+)) subsets. Ligand-receptor analyses highlighted dense inflammatory networks in LLC1 tumors versus metabolically tuned signaling in Kras(LA2) tumors. CONCLUSION: Distinct CD45(+) immune landscapes, characterized by inflammatory suppression in LLC1 and metabolic adaptation in Kras(LA2) tumors, shape lung tumor biology. This atlas identifies genotype-specific immune vulnerabilities with potential relevance for precision immunotherapy in non-small cell lung cancer.
- Dizdarevic, S.
- Wiegandt, R.
- Weigert, A.
- Stiewe, T.
- Eul, B.
- Guenther, S.
- Grimminger, F.
- Seeger, W.
- Pullamsetti, S. S.
- Looso, M.
- Turkowski, K.
- Savai, R.
