Biology subjects

Alimadadi, A.

Publications and source records attributed to Alimadadi, A..

3 recordsLinked to original sources

bioRxiv2026

Targeting phosphodiesterase 10A disrupts MAPK signaling pathways in the tumor microenvironment to unleash antitumor immunity

Phosphodiesterase 10A (PDE10A), a cyclic nucleotide-degrading enzyme, is overexpressed in various human cancers. While PDE10A inhibition using small-molecule inhibitors or gene silencing suppresses tumor growth in xenograft models, its precise mechanism of action and immunological impact remain unclear. Here, we report that ADT-030, a novel PDE10A inhibitor, exhibits potent cytotoxicity against a broad range of murine tumor cell lines. ADT-030 is orally bioavailable and effectively suppresses tumor growth across multiple syngeneic mouse models. Notably, its efficacy is diminished in immunodeficient mice or upon CD8+ T cell depletion, highlighting a critical dependence on host immunity. The immunostimulatory properties of ADT-030 are further supported by its ability to induce immunogenic tumor cell death and promote dendritic cell (DC) maturation, its reliance on Batf3-expressing DCs to elicit antitumor CD8+ T cell response, and its synergy with anti-PD-1 therapy. Comprehensive immune profiling in the 4T1 breast cancer model, both in orthotopic and metastatic settings, revealed that ADT-030 selectively reduces myeloid-derived suppressor cells (MDSCs) while normalizing the immune landscape within the tumor. Mechanistically, ADT-030 disrupts multiple components of the mitogen-activated protein kinase (MAPK) signaling network in both tumor cells and MDSCs, leading to induction of apoptosis in these populations. These findings highlight the multi-faceted impact of PDE10A inhibition as a therapeutic strategy that not only disrupts tumor-intrinsic oncogenic signaling to inhibit tumor progression but also reshapes the tumor immune microenvironment to unleash antitumor immunity.

immunology↗

bioRxiv2022

Modeling the evolutionary history of nonclassical monocytes in mammals

The immune system has experienced major changes in both its organization and function during the evolution of tetrapod animals. Still, the ancestry of specific cell types and the historical relationships between modern immune cells has received little attention. While all tetrapods possess mononuclear blood cells and monocytes, vasculature-patrolling nonclassical monocytes (CD16+CD14- in humans, Ly6C- in mice) have so far only been described in mammals. The question of whether nonclassical monocytes are specific to the mammalian lineage has not been answered. Cell types can be described as traits that persist via the inheritance of core regulatory complexes of transcription factors. We utilized transcriptional network analyses on a human monocyte single-cell RNA-sequencing dataset to highlight the core regulatory complex associated with nonclassical monocyte production (nCoRC). We then applied BLAST-based analyses to quantify the conservation of human nCoRC members amongst mammals and nonmammals. We determined that the average sequence similarity of nCoRC members is highest amongst mammals and that such conservation is not observed in non-mammalian tetrapods. We also discovered that this sequence similarity is specifically driven by boreoeutherian placental mammals. Finally, we found the receptor proteins upstream of nonclassical monocyte assembly are also more homologous in mammals than non-mammals. This work provides an evolutionary model in which the capacity for nonclassical monocyte production is unique to the mammalian lineage.

evolutionary biology↗

bioRxiv2022

Sex differences in coronary artery disease and diabetes revealed by scRNA-Seq and CITE-Seq of human CD4+ T cells

BackgroundDespite the decades-old knowledge that diabetes mellitus (DM) is a major risk factor for cardiovascular disease (CVD), the reasons for this association are only partially understood. Among the immune cells involved in CVD development, accumulating evidence supports the critical role of T cells as drivers and modifiers of this condition. CD4+ T cells are commonly found in atherosclerotic plaques. The activity and distribution of CD4+ T cell subsets differs between the sexes. MethodsPeripheral blood mononuclear cells (PBMCs) of 61 men and women who underwent cardiac catheterization were interrogated by single cell RNA sequencing (scRNA-Seq, [~]200,000 cells) combined with 49 protein markers (CITE-Seq). Coronary artery disease (CAD) was quantified using Gensini scores, with scores above 30 considered CAD+ and below 6 considered CAD-. Four pairs of groups were matched for clinical and demographic parameters. To test how DM changed cell proportions and gene expression, we compared matched groups of diabetic and non-diabetic subjects. We analyzed 41,782 single CD4+ T cell transcriptomes for sex differences in 61 mostly statin-treated coronary artery disease patients with and without DM. ResultsWe identified 16 clusters in CD4 T cells. The proportion of cells in CD4 cluster 8 (CD4T8, CCR2+ Em) was significantly decreased in CAD+, especially among DM+ participants. The proportions of cells in CD4T2, CD4T11, CD4T16 were increased and CD4T13 was decreased in CAD+ among DM+Statin+ participants. CD4T12 was increased in DM+ participants. In female participants, CD4T8, 12, and 13 were decreased compared to in male participants. In CD4 T cells, 31 genes showed significant and coordinated upregulation in both CAD and DM. The DM gene signature was partially additive to the CAD gene signature. ConclusionsWe conclude that CAD and DM are clearly reflected in PBMC transcriptomes and that significant differences exist between women and men and between subjects treated with statins or not.

immunology↗