Targeting Retinoic Acid Signaling for Immunotherapy in Hepatocellular Carcinoma

The objective of this proposal is to examine our hypothesis that inhibition of RA signaling can elicit therapeutic immune responses in hepatocellular carcinoma. We will test this hypothesis in murine models of HCC by (1) reducing RA production with novel RALDH1inhibitors we developed, (2) inhibiting RA signaling with commercially available small molecule inhibitor of RAR/RXR, and (3) boosting T cell responses by anti-PD1. To our knowledge, this would be the first attempt to inhibit RALDH1 for immunotherapy of any cancer. We have made significant progress towards these goals in this reporting period (2021 2022). We demonstrate that our novel RALDH1 inhibitors can abrogate RA production in HCC cells. RA derived from HCC suppressed DC and promoted macrophage differentiation from monocytes; an effect that was reversed upon treatment of HCC cells with our RALDH1-inhibitors. In vivo, our RALDH1 inhibitors reduced immunosuppressive macrophages and suppressed tumor growth in HCC. Finally, we genetic deletion of RALDH1 in HCC and RALDH1inhibitors showed similar tumor suppressive effects in HCC. Taken together, our findings thus far strongly supports RA inhibition as a therapeutic strategy in HCC.