Card9−/− mice had an increased fungal burden, and an antifungal reduced colitis-linked tumorigenesis.

  • Major finding: Card9−/− mice had an increased fungal burden, and an antifungal reduced colitis-linked tumorigenesis.

  • Mechanism: CARD9-deficient myeloid cells exhibit defective inflammasome activation and IL18 maturation.

  • Impact: CARD9 signaling promotes maintenance of the microbial ecology to prevent colitis-associated tumorigenesis.

graphic

Dysregulation of the gut microbiome has been linked to tumorigenesis as well as to inflammatory bowel disease and colitis. Fungi are a significant component of the gut microbiome, and fungal recognition receptors induce downstream innate immune signaling through the common adaptor protein CARD9. However, the role of CARD9-dependent innate immunity in tumorigenesis has not been elucidated. Malik and colleagues found that Card9−/− mice had an increased susceptibility to colitis-associated colon cancer and an impaired immune response during tumorigenesis. Card9−/− mice had an increased fungal burden in the feces, and transferring the microbiota from tumor-bearing Card9−/− mice to wild-type mice increased the rate of colitis-associated tumorigenesis, demonstrating a role for the microbiota in CARD9 deficiency–induced tumorigenesis. Card9−/− macrophages displayed impaired fungicidal abilities in the gut, and Card9−/− mice had an increase in intestinal myeloid-derived suppressor cells (MDSC), which reduced the antitumor immunity. Antifungal treatment suppressed tumorigenesis and reduced MDSC number. Consistent with these findings, in patients with colon cancer, abundance of the commensal fungus C. tropicalis was linked to MDSC proportion. Similarly, in a related study, Wang and colleagues found that CARD9 expression reduced the susceptibility to colitis-associated cancer. CARD9 promoted inflammasome activation in the colon, and CARD9 deficiency reduced IL18 production by myeloid cells to restrict colitis. Mechanistically, CARD9 interacted with the SYK kinase in myeloid cells to promote the production of IL18 and IFNγ by intestinal CD8+ T cells. Adding IL18 or transferring wild-type myeloid cells was sufficient to reduce the tumor burden in Card9−/− mice. Conversely, antifungal treatment suppressed tumorigenesis. Collectively, these findings support a model whereby CARD9 deficiency results in impaired fungal clearing, MDSC accumulation, and suppression of effector T cells, suppressing antitumor immunity to promote colon tumorigenesis.

Malik A, Sharma D, Malireddi RK, Guy CS, Chang TC, Olsen SR, et al. SYK-CARD9 signaling axis promotes gut fungi-mediated inflammasome activation to restrict colitis and colon cancer. Immunity 2018;49:515–30.

Wang T, Fan C, Yao A, Xu X, Zheng G, You Y, et al. The adaptor protein CARD9 protects against colon cancer by restricting mycobiota-mediated expansion of myeloid-derived suppressor cells. Immunity 2018;49:504–14.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.

©2018 American Association for Cancer Research.
2018
American Association for Cancer Research.