Abstract A number of novel cancer treatment strategies have been identified and developed over the last decade with hopes of eradicating a diverse range of cancers, however the molecular mechanisms behind patient immune responses and tumor microenvironment signaling are complex, and have often hindered the translation of these ideas into successful patient treatments. Two modalities at the forefront of these potential blockbuster strategies are combinatorial immunotherapy and epigenetic manipulation. These approaches are supported by compelling clinical data, but have been encumbered by a number of factors including: adverse event profiles, complicated manufacturing and regulatory issues, toxicity due to non-specific small molecule interactions, limited overlap in patient/therapy antigen presentation, and exorbitant cost of biological treatments. To circumvent a number of these limitations, we have taken a novel approach by engineering allogeneic cellular vaccines tailored to specific cancers, that secrete heat-shock protein gp96-Ig and achieve high-frequency polyclonal CD8+ T cell responses to femto-molar concentrations of tumor antigens through antigen cross-priming in vivo. Using genomics (RNA-sequencing) we identified differential mRNA expression levels genome-wide between normal bladder tissue, our proprietary bladder cancer cellular vaccine Vesigenurtacel-L or HS410, and patient bladder tumor biopsy samples, to generate a genomic signature of Bladder Cancer Altered Genes, or BCAGs. Next, we examined a number of small molecule inhibitors of epigenetic modifications (i.e. histone deacetylases or HDACs), and determined their effect on BCAG expression and antigen secretion in HS410 cells. We find that the inhibition of certain HDACs results in decreased proliferation, dampened secretion of gp96-Ig, and attenuated expression of tumor specific genes. Together our work has defined the pattern of gene dysregulation genome-wide in bladder cancer and shown that epigenetic modifiers are capable of modulating the expression of many of these genes, which may be important for the efficacy of our cancer vaccine strategy. Therefore, epigenetic manipulation may present an attractive means to fine-tune gene expression programs and maximize antigen secretion thereby increasing vaccine potency and the ability of a single vaccine to target a variety of cancer types. Citation Format: George J. Fromm, Neal Schilling, Taylor H. Schreiber. Immunotherapy meets epigenetics: GP96-Ig cellular vaccine genetic signature is modulated by the inhibition of histone modifications. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5037. doi:10.1158/1538-7445.AM2015-5037