Humans are symbiotic organisms in which bacteria outnumber eukaryotic cells in a ratio of 10 to 1. Interactions between commensal microorganisms and immune cells at mucosal surfaces forge the orchestration of a robust immune system that is able to defend us from infections. Critical for these interactions are pattern recognition receptors, including TLRs, which exhibit functional polymorphisms in at least 30% of individuals in the general population.
We show that TLR5 recognition of commensal bacteria drives malignant progression at distant, extra-mucosal locations by promoting systemic up-regulation of IL-6, which is further increased through an autocrine loop in reactive tumor cells and drives MDSC mobilization. MDSCs expanded in response to systemic IL-6 elevation produce adenosine to transform T cells into immunosuppressive players that secrete higher levels of galectin-1 on a per cell basis than any other cell type in the tumor microenvironment.
In contrast, in TLR5-unresponsive individuals, there is systemic up-regulation of IL-17 during tumor development. However, this is only relevant for tumor growth when tumors generate relatively low levels of circulating IL-6, resulting in accelerated malignant progression in the absence of TLR5 signaling.
Importantly, depletion of commensal bacteria abrogates any variations in tumor progression and has opposite effects in tumors that grow faster in TLR5-competent individuals (delaying malignant progression) vs. tumors that progress faster in the absence of TLR5 signaling (where malignant progression is accelerated).
Shockingly, depletion of commensal bacteria has opposite effects in the progression of primary vs. metastatic breast tumors, thus opening new avenues to understand breast cancer recurrence and tumor dormancy.
Together, our data indicate that both tumor-promoting inflammation and anti-tumor immunity are influenced by TLR5 signaling, which depends on a common genetic polymorphism in cancer patients.
Citation Format: Melanie R. Rutkowski, Jose R. Conejo-Garcia. Commensal microorganisms and polymorphic mucosal surfaces determine the evolution of distal metastatic tumors. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr IA32.
- ©2016 American Association for Cancer Research.