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

Abstract

Abstract 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 activation 1–3 , 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 ICB 4–9 . 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 response 10–16 . 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 (T H 17) 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 (T H 1)-like cells derived from the homeostatic T H 17 cells induced by SFB colonization in the SILP. These gut-educated ex-T H 17 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 T H 1-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.