| Popis: |
Background: Entinostat, a selective histone deacetylase 1/3 inhibitor has been shown to promote a robust anti-tumor response and increased neoantigen expression and antigen-specific T cell activation in preclinical tumor models. Entinostat plays a role in neutralizing myeloid derived suppressor cells (MDSC) to improve anti-tumor immune response. Entinostat is currently being tested in later-stage clinical trials in various types of cancer. Using a novel 3D ex-vivo platform with fresh patient tumor samples we assessed the therapeutic efficacy of Entinostat with intact stromal components and tumor immune microenvironment. Methods: All tumor samples were obtained with patient consent and relevant IRB approval. Unpropagated 3D tumoroids with intact TME measuring 150 µm in size were prepared from fresh tumor samples from renal cell carcinoma (RCC) patients using a proprietary technology developed at Nilogen Oncosystems. Tumoroids prepared from each patient’s tumor sample were pooled to represent the tumor heterogeneity and treated ex vivo with Entinostat for 48h to detect treatment-mediated changes in tumor immune cell composition including lymphoid and myeloid markers and their activation status. Results: Tumoroids treated with Entinostat increased NK, NKT, CD4 and CD8+T cells compared to untreated control. Ex vivo treatment with Entinostat led to an increase in CD69 and Granzyme B expression in tumor resident CD4+ T cells. Immune checkpoint receptors, 41BB and PD-1 expression was increased in CD8+T cells followed by Entinostat treatment. Decreased monocytic MDSC was seen in Entinostat treated tumoroids compared to untreated control and this was associated with decreased GM-CSF, IL-4, IL-6 cytokine levels and increased IFN-γ and IL-2, quantified by multiplex cytokine assay. Interestingly, the tumor cell killing study revealed a higher percentage of death in early stage MDSC (eMDSC) indicating a direct effect of Entinostat on MDSC survival. Conclusions: These results demonstrate that Entinostat treatment leads to a broad range of immune cell activation and MDSC inhibition in RCC. These data provide a mechanistic rationale utilizing our 3D tumoroid platform for discovery of potential biomarkers of drug sensitivity and to identify novel immunotherapeutic approaches. Clinical applications of 3D-EXplore may help to identify RCC patients who may likely benefit from Entinostat treatment. Citation Format: Krithika Nandakumar Kodumudi, Brittany Bunch, Jared Ehrhart, Matt Weitzman, Olivia MacIntosh, Kelly Sussman, Soner Altiok. Assessment of immunotherapeutic efficacy of entinostat by using the 3d-explore ex vivo platform utilizing tumoroids of fresh patient tumor samples with intact tumor microenvironment [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 239. |
