Biology subjects

Okoko, O. D.

Publications and source records attributed to Okoko, O. D..

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↗

bioRxiv2026

Indomethacin exerts both cyclooxygenase inhibition-dependent and independent mechanisms to enhance chemo-immunotherapy in mice

Nonsteroidal anti-inflammatory drugs (NSAIDs) primarily act by inhibiting cyclooxygenases (COX1 and COX2), thereby reducing production of the proinflammatory mediator prostaglandin E2 (PGE2). Because PGE2 is a critical driver of cancer progression and tumor immune evasion, this has motivated interest in combining NSAIDs with chemotherapy or immunotherapy for cancer treatment. However, since COX and PGE2 levels vary across tumor types, it remains unclear whether tumor PGE2 abundance solely dictates tumor response to NSAID-based therapies. Here, we investigated the therapeutic potential of indomethacin (Indo), a prototypical NSAID, in combination with cyclophosphamide (CTX), a widely used chemotherapeutic agent with immunostimulatory properties. Metronomic administration of Indo significantly enhanced the antitumor efficacy of CTX in multiple murine tumor models exhibiting variable COX2 and PGE2 levels, including CT26, MC38, 4T1 and A20. The antitumor effects of CTX+Indo required CD8 T cells and T-cell trafficking from tumor-draining lymph nodes and were further potentiated by anti-PD-1 blockade. Single-cell RNA sequencing (scRNA-seq) revealed that responsive CT26 tumors exhibited a reprogrammed tumor immune microenvironment (TIME), marked by increased effector CD8 T-cell infiltration, reduced immunosuppressive myeloid populations, and enhanced interferon signaling in tumor cells. Importantly, Indo retained therapeutic benefit following CTX even in tumors incapable of producing PGE2, demonstrating a critical contribution of COX-independent mechanisms, particularly inhibition of tumor-intrinsic oncogenic RAS signaling, to the enhanced efficacy of the CTX+Indo combination. Collectively, our results provide strong preclinical rationale for leveraging the COX/PGE2 and RAS dual inhibitory capacities of NSAIDs to enhance the efficacy of chemotherapy and immunotherapy.

immunology↗

bioRxiv2024

Single-cell transcriptome profiling of the myeloid cells repopulating after chemotherapy identifies a neutrophil-like monocyte subset with pro-tumor activities

Patients with cancer often receive chemotherapy to control tumor progression and reduce disease symptoms. Cytotoxic chemotherapeutic agents not only kill rapidly growing cancer cells but also reduce normal cells including myeloid cells, the main innate immune population involved in fighting infections and repairing tissue damages. Rapid loss of myeloid cells caused by chemotherapy triggers myelopoiesis, a process in which the hematopoietic stem and progenitor cells in the bone marrow regenerate myeloid cells, including monocytes, neutrophils, dendritic cells and macrophages, to reconstitute the myeloid cell compartment. We previously reported that chemotherapy with an alkylating agent cyclophosphamide (CTX) in mice leads to repopulation of myeloid cells that acquire immunosuppressive activities within the monocyte subset. However, detailed information on the cellular composition and molecular identity of these chemotherapy- induced immunosuppressive monocytes is lacking. Here, we investigated how the various myeloid cell subsets in the bone marrow of mice respond to CTX chemotherapy through single-cell RNA sequencing analysis (scRNAseq). We found that myeloid progenitor cells and monocytes were reduced 2 days after chemotherapy but rebounded and surpassed their pretreatment levels by day 7. Further scRNAseq analysis of pre-enriched monocytes revealed that the monocyte population was heterogenous, and that chemotherapy tilted myelopoiesis towards the production of neutrophil-like monocytes (NeuMo). We identified Cxcr4 and Cx3cr1 as suitable markers for isolation of chemotherapy-induced NeuMo and demonstrated that these cells were suppressive to T cells. Together with the evidence that CTX-induced monocytes can promote breast cancer metastasis in mice, our data reveal the heterogeneity of the monocytes reemerging after chemotherapy and identify the NeuMo subset as a potential therapeutic target for enhancing the efficacy of chemotherapy in cancer.

immunology↗