Biology subjects

Pedroza, D. A.

Publications and source records attributed to Pedroza, D. A..

3 recordsLinked to original sources

bioRxiv2026

MERTK inhibition cooperates with immunomodulatory cyclophosphamide to induce CXCL9⁺ monocyte-macrophage programming and durable anti-tumor immunity in triple negative breast cancer

Triple-negative breast cancer (TNBC) has high rates of recurrence despite chemotherapy and immune checkpoint blockade (ICB). Tumor-associated macrophages (TAMs) can either suppress or support anti-tumor immunity, but the mechanisms governing these states and therapeutic targets remain unclear. Here, integrating public scRNAseq datasets with TNBC cohorts, we identify a prognostic myeloid signature defined by CXCL9hi/C1Qlow TAM programs, associated with improved survival and increased lymphocyte activation pathways. Using immunocompetent p53-null syngeneic TNBC models spanning basal-like (2153L) and claudin-low (T12) subtypes, we show that immunomodulatory cyclophosphamide (CTX) reprograms hematopoiesis toward the monocytic lineage and induces an interferon (IFN) conditioned tumor milieu that supports CXCL9 monocyte-derived macrophages (Mo.Macs) in basal-like disease. Combining CTX with the next generation MERTK-selective inhibitor UNC2371 (MRX-2843) drives complete remissions in both models, but durable long-term responses occurred selectively in the basal-like subtype model. The expansion of antigen-presenting CXCL9 Mo.Macs and reduction of C1q phagocytic TAMs are observed in responding tumors. Mechanistically, MERTK inhibition relieves MAPK/SOCS1 mediated restraint of IFN signaling driving a positive feedback loop of IRF7/STAT1/IRF1 driven CXCL9 induction. Functionally, tumor control requires CXCL9-CXCR3 dependent CD4 T cell recruitment, accumulation of stem-like memory CD4 T cells, and germinal center like immune organization in tumor-draining lymph nodes. PD-1 blockade further increases durability, preventing recurrence in most treated basal-like tumors. Together, these findings define an IFN licensed, MERTK regulated myeloid checkpoint that can be therapeutically targeted to convert suppressive TNBC microenvironments into durable adaptive immunity, supporting clinical translation of CTX + MRX-2843 based combinations in basal-like TNBC. SignificanceSuppressive myeloid programing limits effective adaptive immune engagement in TNBC usually resulting in ICB treatment resistance and tumor recurrence. This study identifies a therapeutically actionable myeloid interferon checkpoint in which MERTK inhibition stabilizes CXCL9 monocyte-macrophage programming to promote CD4 T cell dependent immune memory and durable tumor control in basal-like TNBC.

cancer biology↗

bioRxiv2025

Anti-CSF-1R therapy with combined immuno- chemotherapy coordinate an adaptive immune response to eliminate macrophage enriched Triple Negative Breast Cancers

Patients diagnosed with metastatic triple negative breast cancer (mTNBC) have limited treatment options, are more prone to develop resistance and are associated with high mortality. A cold tumor immune microenvironment (TIME) characterized by low T cells and high tumor associated macrophages (TAMs) in mTNBC is associated with the failure of standard-of-care chemotherapy and immune checkpoint blockade (ICB) treatment. We demonstrate that the combination of immunomodulatory metronomic Cyclophosphamide (CTX) coupled with anti-CSF-1R antibody targeted therapy (SNDX-ms6352) and anti-PD-1 (ICB), was highly effective against aggressive metastatic syngeneic Trp53 null TNBC genetically engineered mouse models (GEMMs) that present with high macrophage infiltration. Mechanistically, CSF-1R inhibition along with CTX disrupted the M-CSF/CSF-1R axis which upregulated IL-17, IL-15 and type II interferon resulting in elevated B- and T cell infiltration. Addition of an anti-PD-1 maintenance dose helped overcome de novo PD-L1 intra-tumoral heterogeneity (ITH) associated recurrence in lung and liver mTNBC.

cancer biology↗

bioRxiv2024

CBP/P300 BRD Inhibition Reduces Neutrophil Accumulation and Activates Antitumor Immunity in TNBC

Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain (BRD) of CBP/P300 has been shown to regulate its activity. In this study, we found that IACS-70654, a novel and selective CBP/P300 BRD inhibitor, reduced TANs and inhibited the growth of neutrophil-enriched TNBC models. In the bone marrow, CBP/P300 BRD inhibition reduced the tumor-driven abnormal differentiation and proliferation of neutrophil progenitors. Inhibition of CBP/P300 BRD also stimulated the immune response by inducing an IFN response and MHCI expression in tumor cells and increasing tumor-infiltrated CTLs. Moreover, IACS-70654 improved the response of a neutrophil-enriched TNBC model to docetaxel and immune checkpoint blockade. This provides a rationale for combining a CBP/P300 BRD inhibitor with standard-of-care therapies in future clinical trials for neutrophil-enriched TNBC. SummaryIn neutrophil-enriched triple-negative breast cancer (TNBC) models, CREB binding protein (CBP)/P300 bromodomain (BRD) inhibition reduces tumor growth and systemic neutrophil accumulation while stimulating an antitumor immune response. This improves standard-of-care therapies, suggesting a potential therapeutic benefit of CBP/P300 BRD inhibitors for neutrophil-enriched TNBC.

cancer biology↗