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HDAC6 inhibitor ACY241 evokes transcriptional changes in tumor-associated T cells and macrophages

ABSTRACT: While HDAC inhibitors have shown promise in hematologic cancers, their efficacy remains limited in solid cancers. In the present study, we evaluated the immunomodulatory properties of the HDAC6 inhibitor, Citarinostat (ACY241) on lung tumor immune compartment in Kras and p53 mutant autochthonous murine model of non-small cell lung cancer. Tumor-bearing mice were treated with ACY241 or vehicle as controls after which tumor-associated effector T cells (CD3+CD25low/-) macrophages CD11b+CD11cdimGr-1-) were sorted from lung tumors and subjected to RNA-sequencing. We found that the effect of ACY241 was most pronounced on macrophages compared to T cells. Over 4, 450 genes were differentially expressed in T cells while over 5, 650 genes were differentially regulated in tumor-associated macrophages upon ACY 241 treatment. Among the most upregulated genes are those encoding costimulatory molecules Tnfrsf9, Cd40, Cd80, Cd83; MHC proteins H2-Ab1, H2-DMb1, as well as related proteins Cd1d1, Cd74, Ctsa, and Tpp1. A number of chemokine genes such as Cxcl12, Ccl4, and Ccl22 were also differentially expressed. Furthermore, several downregulated gene transcripts include Tgfbr3, Cd274, Nos, Pdcd4, and Tnfsf10. Our findings suggest that HDAC6 while primarily considered a cytoplasmic protein, has measurable transcriptional activity that is revealed through its inhibition in tumor-associated immune cell subsets..

ORGANISM(S): Mus musculus

PROVIDER: GSE197278 | GEO | 2022/02/23

REPOSITORIES: GEO

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Project description:Background: Macrophage-based cell therapies have shown modest success in clinical trials, which can be attributed to their phenotypic plasticity, where transplanted macrophages get reprogrammed towards a pro-tumor phenotype. In most tumor types, including melanoma, the balance between antitumor M1-like and tumor-promoting M2-like macrophages is critical in defining the local immune response with a higher M1/M2 ratio favoring antitumor immunity. Therefore, designing novel strategies to increase the M1/M2 ratio in the TME has high clinical significance and benefits macrophage-based cell therapies. Methods: In this study, we reprogrammed antitumor and proinflammatory macrophages ex-vivo with HDAC6 inhibitors (HDAC6i). We administered the reprogrammed macrophages intratumorally as an adoptive cell therapy (ACT) in the syngeneic SM1 murine melanoma model and patient-derived xenograft bearing NSG-SGM3 humanized mouse models. We phenotyped the tumor-infiltrated immune cells by flow cytometry and histological analysis of tumor sections for macrophage markers. We performed bulk RNA-seq profiling of murine bone marrow-derived macrophages treated with vehicle or HDAC6i and single-cell RNA-seq profiling of SM1 tumor-infiltrated immune cells to determine the effect of intratumor macrophage ACT on the tumor microenvironment (TME). We further analyzed the single-cell data to identify key cell-cell interactions and trajectory analysis to determine the fate of tumor-associated macrophages post-ACT. Results: Macrophage ACT resulted in diminished tumor growth in both mouse models. We also demonstrated that HDAC6 inhibition in macrophages suppressed the polarization toward tumor-promoting phenotype by attenuating STAT3-mediated M2 reprogramming. Two weeks post-transplantation, ACT macrophages were viable, and inhibition of HDAC6 rendered intratumor transplanted M1 macrophages resistant to repolarization towards protumor M2 phenotype in-vivo. Further characterization of tumors by flow cytometry, single-cell transcriptomics, and single-cell secretome analyses revealed a significant enrichment of antitumor M1-like macrophages, resulting in increased M1/M2 ratio and infiltration of CD8 effector T-cells. Computational analysis of single-cell RNA-seq data for cell-cell interactions and trajectory analyses indicated activation of monocytes and T-cells in the TME. Conclusions: In summary, for the first time, we demonstrated the potential of reprogramming macrophages ex-vivo with HDAC6 inhibitors as a viable macrophage cell therapy to treat solid tumors.

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HDAC6 inhibitor ACY241 evokes transcriptional changes in tumor-associated T cells and macrophages

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