Clonal lineage tracing of innate immune cells in human cancer
Menée à l'aide d'échantillons sanguins ainsi que d'échantillons tissulaires et d'échantillons tumoraux provenant de patientes atteintes d'un cancer de l'ovaire ou de patients atteints d'un cancer du poumon, cette étude décrit une méthode qui exploite les mutations de l'ADN mitochondrial somatique pour reconstituer les relations entre les lignées clonales au sein de tissus humains, examine l'évolution clonale de 218 715 cellules et démontre que des sous-populations de cellules myéloïdes résidant dans le microenvironnement tumoral (macrophages, cellules dendritiques de type 3...) sont clonalement apparentées aux monocytes circulants et à ceux qui infiltrent les tissus
Innate immune cells constitute the majority of the tumor microenvironment (TME) and mediate anti-tumor immunity and immunotherapy responses. While single-cell T and B cell receptor sequencing have revealed insights into the clonal dynamics of adaptive immunity, the lack of analogous tools has precluded similar analysis of innate immune cells. Here, we describe a method leveraging somatic mitochondrial DNA (mtDNA) mutations to reconstruct clonal lineage relationships between cells in native human tissues. By jointly profiling single-cell chromatin accessibility and mtDNA variants, we resolve clonal dynamics of 218,715 cells from matched tumors, tissues, and blood from patients with lung and ovarian cancers. Clonal tracing reveals that TME-resident myeloid subsets, including macrophages and type 3 dendritic cells (DC3), are clonally related to circulating and tissue-infiltrating monocytes. We further identify distinct DC-biased and macrophage-biased clones, whose circulating monocyte precursors exhibit distinct epigenetic profiles, suggesting intratumoral myeloid differentiation fate may be peripherally programmed before TME infiltration.
Cancer Cell , article en libre accès, 2026