Microbiota-induced T cell plasticity enables immune-mediated tumour control

Therapies that harness the immune system to target and eliminate tumour cells have revolutionized cancer care. Immune checkpoint blockade (ICB), which boosts the anti-tumour immune response by inhibiting negative regulators of T cell activation1-3, is remarkably successful in a subset of cancer patients. Yet a significant proportion do not respond to treatment, emphasizing the need to understand factors influencing the therapeutic efficacy of ICB4-9. The gut microbiota, consisting of trillions of microorganisms residing in the gastrointestinal tract, has emerged as a critical determinant of immune function and response to cancer immunotherapy, with several studies demonstrating association of microbiota composition with clinical response10-16. However, a mechanistic understanding of how gut commensal bacteria influence the efficacy of ICB remains elusive. Here we use a gut commensal microorganism, segmented filamentous bacteria (SFB), which induces an antigen-specific T helper 17 (TH17) cell effector program in the small intestine lamina propria (SILP)17, to investigate how colonization with this microbe affects the efficacy of ICB in restraining distal growth of tumours sharing antigen with SFB. We find that anti-programmed cell death protein 1 (PD-1) treatment effectively inhibits the growth of implanted SFB antigen-expressing melanoma only if mice are colonized with SFB. Through T cell receptor (TCR) clonal lineage tracing, fate mapping and peptide-major histocompatability complex (MHC) tetramer staining, we identify tumour-associated SFB-specific T helper 1 (TH1)-like cells derived from the homeostatic TH17 cells induced by SFB colonization in the SILP. These gut-educated ex-TH17 cells produce high levels of the pro-inflammatory cytokines interferon (IFN)-γ and tumour necrosis factor (TNF) within the tumour microenvironment (TME), enhancing antigen presentation and promoting recruitment, expansion and effector functions of CD8+ tumour-infiltrating cytotoxic lymphocytes and thereby enabling anti-PD-1-mediated tumour control. Conditional ablation of SFB-induced IL-17A+CD4+ T cells, precursors of tumour-associated TH1-like cells, abolishes anti-PD-1-mediated tumour control and markedly impairs tumour-specific CD8+ T cell recruitment and effector function within the TME. Our data, as a proof of principle, define a cellular pathway by which a single, defined intestinal commensal imprints T cell plasticity that potentiates PD-1 blockade, and indicate targeted modulation of the microbiota as a strategy to broaden ICB efficacy.