Biology subjects

Yee, S. S.

Publications and source records attributed to Yee, S. S..

3 recordsLinked to original sources

bioRxiv2026

Histotripsy-initiated immune response synergizes with chemotherapy in a neuroblastoma murine model

High-risk neuroblastoma (NB) is a pediatric malignancy associated with metastases and an immunosuppressive tumor microenvironment. Standard-of-care treatments like chemotherapy are often ineffective, which motivates the investigation of adjuvant approaches. Histotripsy is a noninvasive focused ultrasound therapy that ablates tissue through the mechanical action of bubble clouds. In addition to disruption of the targeted tumor, non-targeted lesions exhibit growth delay after the histotripsy procedure. The primary hypothesis of this study was histotripsy-induced shifts in the tumor microenvironment will improve the response of metastatic NB to chemotherapy. Female A/J mice flanks were inoculated bilaterally with 1x10 Neuro-2a cells. Histotripsy was applied to one tumor (200-500 mm3), with or without concurrent administration of liposomal doxorubicin (LDOX). The contralateral tumor served as a model of non-targeted distal metastases. Following treatment, tumors were monitored indefinitely for growth, or assessed after 5-7 days with flow cytometry, single-cell RNA sequencing, and immunohistochemistry. Histotripsy alone delayed the growth of treated and contralateral tumors relative to controls (p = 0.01 and p < 0.0001, respectively) and increased CD8 T and CD11b+ cells (p < 0.05 for both comparisons). Further, NB cells in targeted and contralateral tumors exhibited a decrease in Myc expression and cell-cycle activity, and upregulation of interferon and apoptosis pathways. Histotripsy combined with LDOX had the longest delay in tumor growth (p < 0.01) and greatest expression of CD8 and MOMA staining. These findings indicate that histotripsy induces a systemic antitumor immune response that potentiates chemotherapy efficacy in this model of metastatic NB. SignificanceMechanical ablation with histotripsy drives systemic antitumor immunity, reshapes the tumor microenvironment, and enhances chemotherapy efficacy in a syngeneic model of metastatic, high-risk neuroblastoma.

cancer biology↗

bioRxiv2026

IL-6R blockade with tocilizumab disrupts pericyte-and tumor cell-driven IL-6/STAT3 signaling, enhancing docetaxel efficacy in ER+ breast cancer

Metastatic breast cancer is a global health concern with a persistently low five-year survival rate. Taxane microtubule stabilizers, including docetaxel (DTX), are the standard of care in various treatment protocols. DTX is used both as a single agent and in combination therapies, with a majority of ER+ breast cancer patients ultimately developing chemoresistance. The mechanisms contributing to chemoresistance involving the tumor microenvironment (TME) have not been fully elucidated. Specifically, the role of vascular cells within the TME, particularly pericytes, is understudied, and their role in promoting chemoresistance remains unknown. Inflammatory cytokines such as interleukin 6 (IL-6) are known to drive drug resistance via activation of the pro-survival JAK/STAT pathway. We found that DTX induced IL-6 secretion of pericytes by at least two-fold compared to vehicle-treated controls in vitro. All tested breast cancer cell lines expressed subunits of the IL-6 receptor (IL-6R) complex, indicating their capacity to respond to JAK/STAT signaling. Conditioned media from DTX-treated pericytes activated STAT3 in ER+ breast cancer cells to levels comparable to recombinant IL-6. Pharmacologic blockade of IL-6 signaling with the IL-6R inhibitor, tocilizumab, reduced DTX-induced STAT3 activation in vitro. Furthermore, combined treatment with tocilizumab and DTX synergistically suppressed the growth of zero-passage patient-derived ER+ breast cancer organoids expressing intact IL-6 signaling. Together, our findings suggest that combining DTX with tocilizumab may revert DTX-induced chemoresistance in ER+ breast cancer patients by inhibiting IL-6-mediated activation of the STAT3 pathway.

cancer biology↗

bioRxiv2026

Post-COVID impairment of memory T cell responses to community-acquired pathogens can be rectified by activating cellular metabolism

Infection rates involving bacterial and viral pathogens have increased precipitously after the COVID-19 pandemic. While it has been speculated that higher infection rates resulted from increased hospitalizations throughout the pandemic or greater use of antibiotics, precisely why rates remain high today has remained unexplained. Mitochondrial dysfunction is known to occur post-COVID and may disrupt immune responses. Within T cells, SARS-CoV-2 infection is linked to low mitochondrial membrane potential, increased mitochondrial apoptosis, and decreased mitochondrial respiration, which together impact cellular activation and function beyond the acute phase of illness. Here, we demonstrate that decreased mitochondrial function in antigen-specific T cells post-COVID may contribute to higher infection susceptibility by metabolically immobilizing T cell memory responses. Using donor-matched peripheral blood samples from 31 COVID-naive individuals who subsequently contracted COVID-19, we tracked how influenza A (IAV), Staphylococcus aureus (SA), and Varicella-zoster virus (VZV) T cell responses were impacted by COVID-19 infection. We found that gene expression linked to T cell activation decreased but mitochondrial redox pathways increased in CD4 memory T cells post-COVID. However, mitochondrial flux and reactive oxygen species production were limited in a plurality of post-COVID memory T cells after stimulation with IAV, SA, and VZV. Furthermore, we found a disordered relationship between memory T cell mobilization of glycolysis, fatty acid metabolism, and oxidative phosphorylation pathways post-COVID which resulted in diminished use of catabolic pathways including glycolysis and fatty acid oxidation in antigen-specific T cells. Modulation of mitochondrial function with metformin and ubiquinol partially rescued the post-COVID decline in T cell catabolism. Collectively, these findings indicate that COVID-19 infection may have lasting effects on inhibiting T cell memory responses to commonly encountered community-acquired pathogens which can be corrected with commonly available medications. This has significant implications for the clinical care of immunologically vulnerable populations in the post-pandemic era.

immunology↗