Immunosuppressive and Tumor-Intrinsic Effects of ALDH1a3 Expression by B16-F10 Melanoma Cells

Abstract

Cancer cells are often able to evade immune surveillance, facilitating tumor progression and creating a barrier for developing effective immunotherapy. The secretion of retinoic acid (RA) by tumor cells is known to suppress immune responses by promoting the formation of an immunosuppressive tumor microenvironment (TME). Recent studies have demonstrated that expression levels of aldehyde dehydrogenase family 1, member A2 (ALDH1a2), which converts retinal to RA, is upregulated in tumor-associated dendritic cells (DCs). Furthermore, DCs upregulate ALDH1a2 in response to RA signaling through positive feedback, which is believed to be related to their ability to promote immune tolerance in normal physiology by facilitating the differentiation of regulatory T cells. Considering that many human cancer cell lines express the similar ALDH1a3 isoform, melanoma cells with ALDH1a3 overexpression were generated, and I examined the effect of this enzyme on DC immunogenicity and tumor growth. Using co-culture models of B16-F10 melanoma cells and DCs, I discovered that B16-F10 overexpression of ALDH1a3 leads to decreased expression of the inflammatory markers and T cell stimulators MHCII and CD86, as well as a slight increase in ALDH1a2 expression by DCs, characteristic of a more immunosuppressive phenotype. Intriguingly, I found contrasting results in vivo, in which the growth of B16 tumors was inhibited due to ALDH1a3 expression, suggesting that RA may cause a tumor-intrinsic effect on proliferation or apoptosis as well. I further show that these growth inhibitory effects of ALDH1a3 expression and RA are replicated in 3D tumor spheroid cultures. This study offers novel insight on how the RA signaling pathway impacts both the TME and the cancer cells themselves, highlighting the ALDH enzymes as a potential therapeutic target to combat immune evasion.