CARD9 prevents lung cancer development by suppressing the expansion of myeloid-derived suppressor cells and IDO production.

Caspase recruitment domain-containing protein 9 (CARD9) is an adaptor protein and highly expressed in myeloid cells. Our previous study demonstrates a critical protective effect of CARD9 in the development of colitis-associated colon cancer. Nevertheless, the effect of CARD9 in lung cancer remains unclear. Here, using a mouse Lewis lung cancer model, we found the tumor burden of CARD9^-/- mice was much heavier than that in wild-type (WT) mice. More myeloid-derived suppressor cells (MDSCs) were accumulated and less cytotoxicity T lymphocyte was found in tumor tissues of CARD9^-/- mice, compared to WT mice. Depleting MDSCs using anti-Gr1 antibody can significantly decrease tumor burden in CARD9^-/- mice. Furthermore, the noncanonical nuclear factor-kappaB (NF-κB) pathway was activated in CARD9^-/- mice-derived MDSCs. Deficiency of CARD9 enhanced expression of indoleamine 2,3-dioxygenase (IDO) in MDSCs via noncanonical NF-κB pathway. Moreover, correlations between CARD9 expressions and MDSCs relative genes (IDO, iNOS-2 and arginase 1 [ARG-1]) were further confirmed in tumor tissues from lung cancer patients. Taken together, we showed a CARD9-NF-κB-IDO pathway in MDSCs which can inhibit the suppressive function of MDSCs and prevent lung cancer development.

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