Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment.

The tumor microenvironment (TME) influences cancer progression and therapy response. Therefore, understanding what regulates the TME immune compartment is vital. Here we show that microbiota signals program mononuclear phagocytes in the TME toward immunostimulatory monocytes and dendritic cells (DCs). Single-cell RNA sequencing revealed that absence of microbiota skews the TME toward pro-tumorigenic macrophages. Mechanistically, we show that microbiota-derived stimulator of interferon genes (STING) agonists induce type I interferon (IFN-I) production by intratumoral monocytes to regulate macrophage polarization and natural killer (NK) cell-DC crosstalk. Microbiota modulation with a high-fiber diet triggered the intratumoral IFN-I-NK cell-DC axis and improved the efficacy of immune checkpoint blockade (ICB). We validated our findings in individuals with melanoma treated with ICB and showed that the predicted intratumoral IFN-I and immune compositional differences between responder and non-responder individuals can be transferred by fecal microbiota transplantation. Our study uncovers a mechanistic link between the microbiota and the innate TME that can be harnessed to improve cancer therapies.

Chaotic dynamics for homeostatic hematopoiesis.

Hematopoiesis is a highly dynamical and stochastic process, challenging our understanding of homeostasis. Clinical studies of leukemia or neutropenic patients revealed that multiple blood cell types fluctuate spontaneously with large yet regular oscillations of their frequencies. Yet the stability of hematopoiesis in healthy individuals remains understudied. Here we report on both cross-sectional and longitudinal studies of dozens of healthy mice, through high-dimensional mass and spectral cytometry, to understand hematopoiesis at homeostasis. We found that all cell types in the bone marrow, blood, and spleen exhibit large variations of frequency (e.g., with coefficients of variation larger than 1). While the frequencies of individual cell type fluctuate, there existed extensive and robust correlations/anti-correlations between cell types, exemplified by the pronounced anti-correlation between blood neutrophils and B cells. Through longitudinal study of the blood content of healthy mice, we found that leukocyte fluctuations are ergodic yet subject to chaotic behaviors characterized by a broad spectrum of characteristic timescales. We then built a minimal mathematical model to capture these dynamical features of hematopoiesis (fluctuations, correlations, and chaos) and explain how the accumulation of B cells (e.g. during lymphoma development) would transition the blood cell dynamics from chaos to oscillations (as observed clinically). Finally, we demonstrated the ubiquity and consistency of the correlated fluctuations in hematopoiesis by comparing mouse cohorts of different genetic backgrounds and ages. To conclude, we discuss how study of hematopoiesis must factor in the newfound chaotic dynamics at homeostasis, towards better modeling the responses to perturbations.

IMMUNE AND MOLECULAR CORRELATES OF RESPONSE TO IMMUNOTHERAPY REVEALED BY BRAIN-METASTATIC MELANOMA MODELS.

Despite promising results with immune checkpoint blockade (ICB) therapy, outcomes for patients with brain metastasis (BrM) remain poor. Identifying resistance determinants has been hindered by limited access to patient samples and relevant preclinical models. Here, we developed two mouse melanoma BrM models that reflect the disparate responses to ICB observed in patients. We demonstrate that these models recapitulate the cellular and molecular features of human disease and identify key factors contributing to ICB response. Responsive tumor cells (BR1) expressed inflammatory programs that polarized microglia toward reactive states, characterized by upregulation of MHC-I/-II and immunostimulatory molecules, eliciting robust T cell recruitment. Conversely, resistant melanoma cells (BR3) maintained microglia homeostasis, resulting in poor T cell infiltration. BR1 and BR3 expression signatures correlated positively or negatively with T cell infiltration and BrM patient outcomes, respectively. Our study addresses an unmet need by providing clinically relevant models and uncovering mechanistic insights into BrM ICB responses, identifying potential biomarkers and therapeutic targets.