Immunotherapy efficacy in colorectal cancer is dependent on activation of a microbial-metabolite-immune circuit
Mager, L.; Burkhard, R.; Cooke, N.; Brown, K.; Ramay, H.; Paik, S.; Stagg, J.; Grooves, R.; Gallo, M.; Lewis, I.; Geuking, M.; McCoy, K.
Show abstract
Cancer is a leading cause of death globally. Checkpoint blockade therapies offer a promising treatment for many cancers, but have been ineffective for colorectal cancers. Previous studies have shown a dependency of immunotherapies on the microbiota. Consequently, we hypothesized that specific gut bacteria promote immunotherapy for colorectal cancer. We identify three commensal bacteria and a microbial metabolite, inosine, that enhance the efficacy of immune checkpoint blockade therapy in colorectal cancer. We show that inosine interacts with the adenosine A2A receptor on T cells resulting in intestinal Th1 cell differentiation. Decreased gut barrier function induced by immunotherapy increased the translocation of bacterial metabolites and promoted cancer protective Th1 cell activation. This microbial-metabolite-immune circuit provides a mechanism for a new class of bacteria-enhanced checkpoint blockade therapies. The efficacy of this mechanism differs among colorectal cancer subtypes and highlights the strengths as well as potential limitations of this novel bacterial co-therapy for cancer.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- An mRNA-encoded, long-lasting Interleukin-2 restores CD8+ T cell neoantigen immunity in MHC class I-deficient cancers 96%
- Systematic Elucidation and Pharmacological Targeting of Tumor-Infiltrating Regulatory T Cell Master Regulators 96%
- Spatiotemporal co-dependency between macrophages and exhausted CD8+ T cells in cancer 96%
Similar papers in this journal
- Neoantigen-driven B cell and CD4+ T follicular helper cell collaboration promotes robust anti-tumor CD8+ T cell responses 96%
- Serum Amyloid A Proteins Induce Pathogenic TH17 Cells and Promote Inflammatory Disease 95%
- Human colorectal pre-cancer atlas identifies distinct molecular programs underlying two major subclasses of pre-malignant tumors 95%
Similar papers in this journal
- Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors 96%
- Regulatory T cells crosstalk with tumor and endothelium through lymphotoxin signaling 96%
- In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer 96%
Similar papers in this journal
- VPS9D1-AS1 overexpression amplifies intratumoral TGF-β signaling and promotes tumor cell escape from CD8+ T cell killing in colorectal cancer 96%
- Tissue-resident NK cells support survival in pancreatic cancer through promotion of cDC1-CD8T activity 95%
- Gene interaction perturbation network deciphers a high-resolution taxonomy in colorectal cancer 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.