Abstract 1088: Unleashing the potential of HDACi to augment immunotherapy for the treatment of colorectal cancer
Authors: Holay Nisha , Giri Uma , Miljanic Mihailo , Soleimani Milad , Shaikh Omar , Capasso Anna , Berg Carla L. Van Den , Eckhardt Gail , Triplett Todd 
Published: August 2019

Immunotherapy (IMT) has produced complete responses in a subset of colorectal cancer (CRC) patients harboring tumors molecularly characterized as microsatellite instable (MSI). However, the majority (95%) of CRC patients with microsatellite stable (MSS) tumors remain virtually unresponsive. There is strong rationale that with the correct approach, IMT can elicit potent anti-tumor responses in CRC-MSS patients. Prior studies have demonstrated that histone deacetylase inhibitors (HDACi) have the potential to enhance tumor immunogenicity as indicated by the decreased effectiveness of monotherapy in the absence of an adaptive immune system and augmentation of responses to IMT. Whether HDACi treatment enhances anti-tumor immune responses by increasing tumor immunogenicity, directly affecting T-cells, or both, remains unknown. Therefore, we explored the differential effects of HDAC inhibitors with distinct specificities have directly on tumor and T-cells which will be critical in designing optimal therapeutic strategies.

Results: First, we compared the direct cytotoxic effects on murine CRC cells and found that pan-HDACi caused cell death, while class I/II and HDAC VI inhibitors did not affect survival even at high concentrations (1μM). Evaluation of changes to immunogenic proteins revealed modest, but similar increases in immunogenic proteins (MHC-I, ICOSL, PD1L, CD80) across HDACi compounds. Strikingly, the co-stimulatory ligand CD86 was increased only with an HDAC VI inhibitor. Next, we sought to determine whether distinct inhibitors also had direct effects on T-cells during stimulation. Interestingly, we found all inhibitors did not affect TNFα production but caused a drastic decrease in IL-2, an important cytokine for T-cell survival and function. Moreover, this effect was found at low concentrations of HDACi and thus appear more sensitive.

Conclusions: These results demonstrate for the first time that different classes of HDAC inhibitors have unique properties in affecting tumor growth and immunogenicity. Conversely, all classes blocked IL-2 production by T-cells but not TNFα, suggesting a common mechanism in affecting select components of T-cell effector responses. Although previous studies showed synergy with IMT, our data suggests that HDACi detrimentally affect T-cells directly. Based on this, an optimal strategy for combination with IMT may entail priming the tumor microenvironment and stopping HDACi during T-cell targeted IMT. Future studies are underway to determine whether HDACi effects on T-cells are reversible, the kinetics of these effects and their impact on T-cell co-receptor expression. Collectively, these studies will help identify the most promising HDACi, immunotherapeutic targets and the sequence of combination therapy.

Citation Format: Nisha Holay, Uma Giri, Mihailo Miljanic, Milad Soleimani, Omar Shaikh, Anna Capasso, Carla L. Van Den Berg, Gail Eckhardt, Todd Triplett. Unleashing the potential of HDACi to augment immunotherapy for the treatment of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1088.