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

Anti-PD-1 treatment effectively inhibits growth of SFB antigen-expressing melanoma only in mice colonized with SFB.

• Implanted melanoma cells were engineered to express SFB antigen, creating a shared antigen system between the gut commensal and the tumour.
• SFB-colonized mice showed significant tumour growth restraint with anti-PD-1 treatment compared to non-colonized mice receiving the same treatment.
• Non-colonized mice failed to respond to anti-PD-1 blockade against SFB antigen-expressing tumours, demonstrating a colonization-dependent effect.

TCR clonal lineage tracing, fate mapping, and peptide-MHC tetramer staining identified tumour-associated TH1-like cells derived from SFB-induced intestinal TH17 cells.

• SFB colonization induces antigen-specific TH17 cells in the small intestine lamina propria (SILP).
• These intestinal TH17 cells undergo plasticity and convert to TH1-like cells within the tumour microenvironment, identified as 'ex-TH17' cells.
• TCR clonal lineage tracing confirmed shared clonotypic identity between SILP TH17 cells and tumour-associated TH1-like cells.
• Peptide-MHC tetramer staining confirmed SFB antigen-specificity of tumour-infiltrating TH1-like cells.

Tumour-associated ex-TH17 cells produce high levels of IFN-γ and TNF within the tumour microenvironment.

• Ex-TH17 cells within the TME expressed pro-inflammatory cytokines IFN-γ and TNF at high levels.
• These cytokines enhanced antigen presentation within the tumour microenvironment.
• IFN-γ and TNF production by ex-TH17 cells promoted recruitment, expansion, and effector functions of CD8+ tumour-infiltrating cytotoxic lymphocytes.

Conditional ablation of SFB-induced IL-17A+CD4+ T cells abolished anti-PD-1-mediated tumour control.

• IL-17A+CD4+ T cells in SFB-colonized mice were identified as the precursors of tumour-associated TH1-like cells.
• Conditional ablation of these IL-17A+CD4+ T cells completely abolished anti-PD-1-mediated tumour control.
• Ablation of these precursor cells markedly impaired tumour-specific CD8+ T cell recruitment and effector function within the TME.
• This experiment established a causal role for SFB-induced TH17 cells in mediating the microbiota-dependent ICB response.

Gut commensal bacteria influence ICB efficacy through a defined cellular pathway involving T cell plasticity.

• The study provides a mechanistic explanation for the previously observed association between microbiota composition and clinical response to ICB.
• The pathway proceeds from intestinal TH17 cell induction by SFB colonization, to T cell plasticity generating ex-TH17/TH1-like cells, to enhanced CD8+ cytotoxic T cell activity in the TME.
• The authors describe these findings as 'a proof of principle' defining 'a cellular pathway by which a single, defined intestinal commensal imprints T cell plasticity that potentiates PD-1 blockade.'
• Results indicate that targeted modulation of the microbiota may represent a strategy to broaden ICB efficacy in non-responding patients.

The gut microbiota, particularly SFB, shapes systemic anti-tumour immunity through antigen-sharing between commensal bacteria and tumour cells.

• SFB induces antigen-specific TH17 effector programs in the SILP under homeostatic conditions.
• When tumours express antigens shared with SFB, these pre-existing gut-educated T cells can be recruited to and activated within the TME.
• This mechanism demonstrates how gut-educated T cells can operate at distal tumour sites, not just at mucosal surfaces.
• The model relies on molecular mimicry or direct antigen sharing between the intestinal commensal organism and the tumour.