Role of microbiota in leukemia.
Leukemia stem cells (LSCs) resist both therapy and immune-mediated elimination. However, the mechanisms by which they evade cytotoxic T cell (CTL) attack are poorly understood. Here, we demonstrate that specific, low-abundance Gram-negative intestinal commensals of the genus Sutterella suppress the anti-leukemic immune response in chronic myeloid leukemia (CML). We found that germ-free and specific opportunistic pathogen-free (SOPF) mice are protected from CML progression. However, colonization of SOPF mice with various Sutterella strains, but not other bacterial strains, restored disease development. Increased prevalence of Sutterella was associated with MyD88/TRIF-dependent CTL exhaustion in specific pathogen-free CML mice. This was evidenced by elevated expression of exhaustion markers, diminished interferon-gamma and granzyme B, reduced LSC-killing capacity ex vivo, and transcriptomic signatures indicative of CTL exhaustion. These findings reveal a connection between gut microbiota and regulation of LSCs by the immune system, identifying Sutterella genus as critical regulator of anti-leukemic immunity in CML.