Specific dendritic cells spatial organization is associated to ICB Response in Non–Small-Cell Lung Cancer

Dendritic cells (DCs) are central orchestrators of antitumor immunity. Several DC subsets—including conventional type 1 (cDC1), conventional type 2 (cDC2), plasmacytoid DCs (pDCs), and mature DC populations—play distinct roles in immune surveillance, tumor control, immunotherapy response and prognosis. Recent findings suggest that cDC1 are spatially closed to CD8⁺ T-cell and contribute to tertiary lymphoid structure formation in lung cancer. However, how other DC subsets interact with cDC1 to shape the tumor microenvironment (TME) remains largely unknown. Here, we analyzed the spatial distribution of major DC subsets, including cDC1, cDC2, mature DC and pDC, together with CD8⁺ T cells in a cohort of anti-PD1-treated NSCLC patients and we deciphered the corresponding immune microenvironment behavior by paired transcriptomic analysis. We found that, while other DC subsets populated the stroma, cDC2 were localized both in the stroma and in tumor nests. Moreover, unlike other DC subsets, cDC2 abundancy did not affect ICB response both at transcriptomic and in situ analysis. We described spatial organization of DCs in megaclusters characterized by distinct proportions of DC subsets. Patients enriched in megaclusters involving variable proportion of pDC, cDC1 and mature DC, exhibited pro-inflammatory transcriptomic programs while those enriched in cDC2-based megaclusters showed limited immune activation features. Globally, DC in lung cancer were structured around three distinct DC spatial patterns, namely cDC1-driven, cDC2-driven and DC-Scattered, each defined by unique compositions of DC megaclusters, immune features and pathways activation profiles. Among them, the cDC1-driven pattern was associated to prolonged anti-PD1 response in two independent cohorts.