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Characterizing the Immunosuppressive Effect of Tumor-Derived Retinoic Acid on Dendritic Cells Larry Shue, Cao Fang, Yibin Kang 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 alcohol dehydrogenase family1, member A2 (ALDH1a2), which converts retinal to RA, is upregulated in tumor-associated dendritic cells (DCs) in response to RA signaling, which promotes regulatory T cell differentiation and immune tolerance. Considering that most human cancer cell lines express a similar ALDH1a3 isoform, it is hypothesized that cancer cells secrete RA to induce an immunosuppressive TME by upregulating ALDH1a2 expression in tumor-associated DCs, shifting them towards a more regulatory phenotype. Co-cultures of B16-F10 melanoma cells with or without ALDH1a3 overexpression and murine bone marrow cells revealed no change in the proportion of DC differentiation, although DC ALDH1a2 expression increased when co-cultured with B16-1a3 cells. Interestingly, the presence of any tumor cells in the co-culture significantly increased neutrophil differentiation. In an in vivo experiment, B16-MCS or B16-1a3 cells were injected subcutaneously into the flanks of B6 mice, and ALDH1a3 appeared to slow tumor growth, hinting at an immune-unrelated effect of ALDH. Further characterization of the co-cultured and tumor-associated DCs will uncover whether they are phenotypically affected by the tumor- derived RA signaling pathway, potentially revealing a mechanism in which cancer cells accomplish immune escape.

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Princeton

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8 Author