A specific bacterium found inside liver tumors can organize the immune microenvironment in ways that improve responses to checkpoint blockade, according to a study published August 17 in Cancer Cell by researchers at Nanjing Medical University led by corresponding author Yun Chen. The work identifies Bacillus cereus as an upstream driver of a distinct immune niche in hepatocellular carcinoma (HCC) and traces the effect to a bacterial enzyme that could offer a more tractable therapeutic approach than administering live bacteria.
The study addresses heterogeneity in tertiary lymphoid structures (TLS), which are generally associated with improved cancer outcomes but do not uniformly predict response to immunotherapy in HCC. The researchers identified a functionally distinct TLS subtype, termed a stem-like lymphoid niche (SLN), characterized by spatial co-localization of CD70-expressing type 2 innate lymphoid cells (ILC2s) and TCF-1-positive progenitor exhausted T cells (Tpex). SLN abundance was associated with response to checkpoint blockade.
Profiling of treatment-naive HCC tumors identified B. cereus as significantly enriched in SLN-high tumors. Fluorescence in situ hybridization confirmed the bacterium within tumor tissue and in proximity to TLS, while imaging mass cytometry identified ILC2s as a spatially enriched population within the structures.
Mechanistically, the researchers traced SLN formation to phosphoinositide-specific phospholipase C (PI-PLC) secreted by B. cereus. PI-PLC removes the complement inhibitor CD55 from tumor endothelial cells, activating complement and triggering endothelial IL-33 release. IL-33 signaling through the ST2 receptor then induces metabolic and epigenetic reprogramming of ILC2s, generating a CD70-positive, lymphotoxin-expressing phenotype that helps organize the SLN. CD70-CD27 co-stimulation also maintains TCF-1 expression in Tpex cells, preserving a progenitor T cell population capable of responding to PD-1/PD-L1 blockade.
The causal role of bacterial PI-PLC was supported in mouse models. Oral administration of B. cereus inhibited tumor growth, increased SLN formation, and enhanced CD8-positive T cell infiltration, while these effects were lost with a PI-PLC-deficient bacterial strain. Intratumoral administration of purified recombinant PI-PLC reproduced the tumor-suppressive and immune-organizing effects of live bacteria. Both B. cereus and recombinant PI-PLC also enhanced the antitumor activity of anti-PD-L1 treatment.