Cross-Reactive Gut Bacteriophage Protein Enhances Anticancer Therapy

Some intestinal microbes may produce antigens that exhibit cross-reactivity with cancer-associated antigens, potentially aiding antitumor immunity. Recent work has suggested that intestinal microbiota may have an impact on the efficacy of some anticancer treatments, perhaps not only via gut-specific immune responses but also through modulation of systemic immunity. Fluckiger and colleagues found that the genomes of some strains of the commensal gut bacterial species Enterococcus hirae harbor a prophage encoding the tail-length tape measure protein (TMP) of the corresponding bacteriophage. The TMP contains an MHC class I–restricted epitope that elicited a CD8⁺ T-cell response in a mouse model of sarcoma when combined with cyclophosphamide or anti–PD-1. This immune response may have been due to cross-reactivity with a cancer-specific antigen, and further experiments supported this notion. For example, gut colonization of mice with Escherichia coli (which normally does not enhance response to anticancer therapies) expressing the immunogenic epitope of TMP (TMP1) produced the same results as colonization with the aforementioned strains of E. hirae. Mutations in TMP1, whether naturally occurring or engineered, abolished the therapeutic benefits of TMP1-expressing E. hirae and E. coli. Additionally, tumors grown from cancer cells engineered to lack the cross-reactive epitope in the protein PSMB4 were resistant to the therapy-enhancing effects of TMP1-expressing E. hirae. Finally, patients with renal or lung cancer who harbored TMP-expressing enterococcal prophage in their stool and whose tumors expressed an antigen cross-reactive with TMP1 exhibited a greater duration of benefit from anti–PD-1 treatment. In summary, this work demonstrates a clear link between a gut microbe and response to anticancer therapy and elucidates a mechanism connecting colonization with this microbe to treatment response.

Fluckiger A, Daillère R, Sassi M, Sixt BS, Liu P, Loos F, et al. Cross-reactivity between tumor MHC class I–restricted antigens and an enterococcal bacteriophage. Science 2020;369:936–42.

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