Abstract 4226: Effect of HDAC6 inhibition on the expression of immunomodulator genes in colorectal cancer cells
Authors: Mardones Constanza , Navarrete Camila , Armijo Estrella , Rivas Fernando , Hepp Matias Ignacio 
Published: June 2022

Cancer is one of the most frequent disease worldwide and currently, treatment failures are caused by pharmacological resistance or low success rate of conventional approaches. In particular, colorectal cancer (CRC) is one of the most common malignant neoplasm in Chile and according to the WHO, represents the second cause of death from tumors in the world, which is why there is a need to study new strategies for future therapies, like the immunotherapy aimed at inhibiting the immune checkpoints, as Programmed Death 1 (PD-1) receptor in T-cell, that interact with his ligand (PD-L1) in the tumor. However, there is a percentage of patients who don't respond to this therapy, making it necessary to search for alternative or adjuvant treatments. Histone deacetylase 6 (HDAC6), a mainly cytoplasmic protein, is involved in several cellular processes including the immune response, being involve in tumor progression. Specifically, it has been observed that HDAC6 stimulates STAT3 activity, a transcription factor involved in immunogenicity, which plays a role as a transcriptional inducer of different genes in these pathways, as PD-L1 (programmed death ligand 1). The over-expression of PD-L1 on some cancer cells promotes inhibition of T lymphocyte activation which reduces the immune response. Therefore, we will focus on pharmacological inhibition of HDAC6 in CRC cell due to its potential as adjuvants to avoid immunotolerance in cancer immunotherapy. Here, we investigate whether HDAC6 affects STAT3 activation in CRC cells, through treatments with Nexturastat A (NextA), a specific HDAC6 inhibitor, that indirectly, decreases the levels of activating post-translational modifications on STAT3 analyzed by Western blot and flow cytometry. In the same context, we analyze by RT-qPCR the decrease in the expression of IL-10 and PD-L1 after NextA treatment. Then to emulate an inflammatory environment, we treat the cells with Interleukin-6 (IL-6) and then with NextA, observing the changes described above over the STAT3 modification and activity. Finally, through a RNAseq assay with the last conditions, showed a reduced the expression of other genes involved in immunomodulatory pathways. These results suggest that treatments with specific HDAC6 inhibitors would reduce the functionality of STAT3 in CRC cells, impacting the expression of immunomodulator genes involved in the immune response, as IL-10, PD-L1 and others. Therefore, the use of specific HDAC6 inhibitors may be a reasonable and an interesting adjuvant strategy for help in checkpoint inhibitors immunotherapy, since HDAC6 inhibitors would indirectly decrease PD-L1 expression, one of the checkpoint inhibitors of immune system.

Citation Format: Constanza Mardones, Camila Navarrete, Estrella Armijo, Fernando Rivas, Matias Ignacio Hepp. Effect of HDAC6 inhibition on the expression of immunomodulator genes in colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4226.