Divergent tumor immunity determined by bacteria-cancer cell engagement

Area of Science:

• Oncology
• Microbiology
• Immunology

Background:

• Intratumor bacteria are increasingly recognized as key players in the cancer ecosystem.
• The spatial location of bacteria within tumors can significantly influence host-pathogen interactions and cancer progression.

Purpose of the Study:

• To investigate the distinct roles of intracellular versus extracellular bacteria in breast cancer metastasis.
• To elucidate the molecular mechanisms by which bacteria influence tumor immunity and host response.

Main Methods:

• Utilized PyMT breast tumor models to study bacterial localization and host immune responses.
• Analyzed the activation of the cGAS-STING-IL-17B pathway and neutrophil behavior in response to bacterial presence.
• Developed and validated a bacteria invasion signature for clinical correlation.

Main Results:

• Intracellular bacteria promote metastasis by inducing cytosolic DNA accumulation, activating the cGAS-STING pathway, and promoting protumor neutrophils that suppress cytotoxic T cells.
• Extracellular bacteria, conversely, induce antitumor neutrophil activity without STING pathway activation.
• Eliminating intracellular bacteria or using extracellular bacterial components abrogated immunosuppression and prevented metastatic recurrence in preclinical models.
• A developed bacteria invasion signature correlated with poor prognosis in breast cancer patients.

Conclusions:

• The spatial localization of bacteria within the tumor microenvironment dictates their impact on cancer immunity and metastasis.
• Targeting bacterial localization or modulating bacterial components offers a potential therapeutic strategy to overcome cancer-induced immunosuppression and prevent metastasis.