Divergent tumor immunity determined by bacteria-cancer cell engagement

 Highlights

• Intratumor bacteria promote breast cancer metastatic recurrence in a preclinical model

• Cytosolic bacteria induce immune suppressive neutrophils via cGAS-STING-IL-17B

• Intra- and extracellular bacteria can play opposite roles in determining neutrophil states

• A bacteria invasion signature is associated with poor prognosis in breast cancer patients

Summary

Intratumor bacteria represent an understudied yet influential component of the cancer ecosystem, critically impinging cancer progression. In PyMT breast tumors, we find intracellular bacteria, when residing in cancer cell cytosol, promote metastasis by triggering cytosolic double-stranded DNA (dsDNA) accumulation, which in turn activates the tumor intrinsic cGAS-STING-interleukin (IL)-17B pathway and redirects neutrophils toward a protumor phenotype that inhibits cytotoxic T cells. By contrast, the same strain of bacteria, when present extracellularly, induces antitumor neutrophil activity without engaging the STING pathway. Physiologically, eliminating intracellular bacteria, or therapeutically introducing extracellular bacteria components, abrogates immunosuppression and prevents postsurgical metastatic recurrence in preclinical models. Clinically, the bacteria invasion signature we have developed is associated with poor prognosis in patients with breast cancer. In summary, the spatial interplay between bacteria and host cells in metastatic niches can shape divergent tumor immunity, highlighting bacterial-host engagement as a crucial determinant of cancer immune regulation and a potential therapeutic target.

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https://www.sciencedirect.com/science/article/abs/pii/S009286742501493X