Low abundant intestinal commensals modulate immune control of chronic myeloid leukemia stem cells

Abstract

Leukemia stem cells (LSCs) are resistant to therapy and immune control. The reason for their resistance to elimination by cytotoxic T cells (CTLs) remains unclear. This study shows that specific low abundant Gram-negative intestinal commensals of the genus Sutterella suppress the anti-leukemia immune response in chronic myeloid leukemia (CML). We found that germ-free and specific opportunistic pathogen-free (SOPF) mice are protected from CML development and that colonization of SOPF mice with Sutterella wadsworthensis, but not other related and unrelated bacterial strains, rescues CML development. A higher prevalence of this microbe resulted in Myd88/TRIF-mediated CTL exhaustion in SPF compared to SOPF CML mice as evidenced by higher surface expression of exhaustion markers on CTLs, a reduced capacity to produce interferon-gamma and granzyme B and to kill LSCs in vitro. These findings provide new insights into the immune control of LSCs and identify Sutterella species as regulators of anti-leukemic immunity in CML.