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Abstract Background Epidemiological studies associate an increase in breast cancer risk, particularly triple-negative breast cancer (TNBC), with lack of breastfeeding. This is more prevalent in African American women, with significantly lower rate of breastfeeding compared to Caucasian women. Prolonged breastfeeding leads to gradual involution (GI), whereas short-term or lack of breastfeeding leads to abrupt involution (AI) of the breast. Our previous study utilizing a murine model demonstrated precancerous changes, specifically hyperplasia, a non-obligate precursor of breast cancer in the mammary glands of AI mice. Here we investigated mechanisms during early events of AI that prompts precancerous changes in mouse mammary glands. Methods Uniparous FVB/N mice were randomized to AI and GI on postpartum day 7 when all pups were removed from AI dams. GI dams were allowed to nurse the pups till day 31. Cell death kinetics and gene expression were assessed by TUNEL assay and qPCR respectively. Immune cell changes were investigated by flow cytometry, cytokine array and multiplex immunofluorescence. 3D-organoid cultures were used for in vitro assay of luminal progenitor cells. Results AI results in rapid cell death, DNA repair response, and immunosuppressive myeloid cells infiltration, leading to a chronically inflamed microenvironment. GI elicits a more controlled immune response and extended cell death. At the peak of cell death, AI glands harbored more immunosuppressive myeloid-derived suppressor cells (MDSCs) and CD206 + M2-like macrophages, known to promote oncogenic events, compared to GI glands. AI glands exhibit an enrichment of CCL9-producing MDSCs and CD206 + M2-like macrophages that promote expansion of ELF5 + /ERα- luminal cells, both in vitro and in vivo. Multiplex imaging of AI glands demonstrated an increase in ELF5 + /WNT5a + luminal cells alongside a reduction in the ELF5 + /ERα + population when involution appeared histologically complete. A significantly higher number of CD206 + cells in post involution AI gland attests to a chronically inflamed state induced by AI. Conclusions Our findings reveal significant disparities between AI and GI gland dynamics at the early phase of involution. CCL9, secreted by immune cells at the peak of cell death promotes expansion of Elf5 + /ERα- luminal progenitor cells, the putative precursors of TNBC connecting early events of AI with increased breast cancer risk.

Abstract Background Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation, tissue damage, and fibrosis, significantly affecting the quality of life. While there are currently some effective treatments available, they often come with side effects. There is an urgent need to find new treatments that can further improve therapeutic outcomes and reduce side effects. Methods Our study investigates the role of Mesenchymal Stem Cell exosomes (MSC-exo) combined with Ginsenoside Rh2 (Rh2) in the treatment of RA. We specifically focus on how this combined strategy influences macrophage polarization and pyroptosis. This research utilized a collagen-induced rat arthritis model. Results The study findings reveal that the combination of MSC-exo combined with Rh2 can inhibit the polarization of M1 macrophages, increase the proportion of M2-like macrophages, and suppress M1-like macrophage pyroptosis via the NLRP3/Caspase11/GSDMD-N pathway. In the rat arthritis model, the combination of MSC-exo and Rh2 showed synergistic therapeutic effects. Conclusion This research contributes to a deeper understanding of RA’s pathogenesis and presents new potential targeted therapeutic interventions. The combined application of MSC-exo and Rh2 offers promising insights for future innovative strategies in RA treatment, paving the way for more effective management of this autoimmune disease.

Abstract Pazopanib (PAZ), an oral multi-tyrosine kinase inhibitor, demonstrates promising cytostatic activities against various human cancers. However, its clinical utility is limited by substantial side effects and therapeutic resistance. We developed a nanoplatform capable of delivering PAZ for enhanced anti-breast cancer therapy. Nanometer-sized PAZ@Fe-MOF, compared to free PAZ, demonstrated increased anti-tumor therapeutic activities in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. High-throughput single-cell RNA sequencing (scRNAseq) revealed that PAZ@Fe-MOF significantly reduced pro-tumorigenic M2-like macrophage populations at tumor sites and suppressed M2-type signaling pathways, such as ATF6-TGFBR1-SMAD3, as well as chemokines including CCL17, CCL22, and CCL24. PAZ@Fe-MOF reprogramed the inhibitory immune microenvironment and curbed tumorigenicity by blocking the polarization of M2 phenotype macrophages. This platform offers a promising and new strategy for improving the cytotoxicity of PAZ against breast cancers. It provides a method to evaluate the immunological response of tumor cells to PAZ-mediated treatment.

Abstract Background The tumor microenvironment is characterized by inflammation-like and immunosuppression situations. Although cancer-associated fibroblasts (CAFs) are among the major stromal cell types in various solid cancers, including colon cancer, the interactions between CAFs and immune cells remains largely uncharacterized. Pentraxin 3 (PTX3) is responsive to proinflammatory cytokines and modulates immunity and tissue remodeling, but its involvement in tumor progression appears to be context-dependent and is unclear. Methods Open-access databases were utilized to examine the association of PTX3 expression and the fibroblast signature in colon cancer. Loss-of-function assays, including studies in tamoxifen-induced Ptx3 knockout mice and treatment with an anti-PTX3 neutralizing antibody (WHC-001), were conducted to assess the involvement of PTX3 in colon cancer progression as well as its immunosuppressive effect. Finally, bioinformatic analyses and in vitro assays were performed to reveal the downstream effectors and decipher the involvement of the CREB1/CEBPB axis in response to PTX3 and PTX3-induced promotion of M2 macrophage polarization. Results Clinically, higher PTX3 expression was positively correlated with fibroblasts and inflammatory response signatures and associated with a poor survival outcome in colon cancer patients. Blockade of PTX3 significantly reduced stromal cell-mediated tumor development. The decrease of the M2 macrophage population and an increase of the cytotoxic CD8+ T-cell population were observed following PTX3 inactivation in allografted colon tumors. We further revealed that activation of cyclic AMP-responsive element-binding protein 1 (CREB1) mediated the PTX3-induced promotion of M2 macrophage polarization. Conclusions PTX3 contributes to stromal cell-mediated protumor immunity by increasing M2-like macrophage polarization, and inhibition of PTX3 with WHC-001 is a potential therapeutic strategy for colon cancer.

Abstract Background Although impaired myeloid-derived suppressor cells (MDSCs) recently have been studied in immune thrombocytopenia (ITP), another myeloid-derived cell population signified as M2 macrophages has not been investigated properly in ITP patients. In the present study, we intended to determine the features of circulating M2-like macrophages, to examine its relationship with MDSCs, and to explore their prognostic values in ITP. Methods Peripheral blood mononuclear cells from healthy controls and primary ITP patients were isolated to test the circulating M2-like macrophages and MDSCs. The circulating M2-like macrophage population defined as CD68+CD163+ and circulating MDSC population as CD11b+CD33+HLA-DR− were determined by flow cytometry. Plasma inflammatory cytokines were measured by multiplex ELISA. Results The percentages of MDSCs were found to be expanded in newly diagnosed patients of ITP, especially among those of the complete response (CR) group (p