Biology subjects

Carson, W. E.

Publications and source records attributed to Carson, W. E..

3 recordsLinked to original sources

bioRxiv2024

A widespread electrical brain network encodes anxiety in health and depressive states

In rodents, anxiety is characterized by heightened vigilance during low-threat and uncertain situations. Though activity in the frontal cortex and limbic system is fundamental to supporting this internal state, the underlying network architecture that integrates activity across brain regions to encode anxiety across animals and paradigms remains unclear. Here, we utilize parallel electrical recordings in freely behaving mice, multiple translational paradigms known to induce anxiety, and machine learning to discover a multi-region network that encodes the anxious brain state. The network is composed of circuits widely implicated in anxiety behavior, it generalizes across many behavioral contexts that induce anxiety, and it fails to encode multiple behavioral contexts that do not. Strikingly, the activity of this network is also principally altered in two mouse models of depression. Thus, we establish a network-level process whereby the brain encodes anxiety in health and disease.

neuroscience↗

bioRxiv2024

Trabectedin Enhances Oncolytic Virotherapy by Reducing Barriers to Virus Spread and Cytotoxic Immunity in Preclinical Pediatric Bone Sarcoma

We previously reported that the DNA alkylator and transcriptional-blocking chemotherapeutic agent trabectedin enhances oncolytic herpes simplex viroimmunotherapy in human sarcoma xenograft models, though the mechanism remained to be elucidated. Here we report trabectedin disrupts the intrinsic cellular anti-viral response which increases viral transcript spread throughout the human tumor cells. We also extended our synergy findings to syngeneic murine sarcoma models, which are poorly susceptible to virus infection. In the absence of robust virus replication, we found trabectedin enhanced viroimmunotherapy efficacy by reducing immunosuppressive macrophages and stimulating granzyme expression in infiltrating T and NK cells to cause immune-mediated tumor regressions. Thus, trabectedin enhances both the direct virus-mediated killing of tumor cells and the viral-induced activation of cytotoxic effector lymphocytes to cause tumor regressions across models. Our data provide a strong rationale for clinical translation as both mechanisms should be simultaneously active in human patients.

cancer biology↗

bioRxiv2020

Dual blockade of IL-6 and CTLA-4 regresses pancreatic tumors in a CD4+ T cell-dependent manner.

Pancreatic ductal adenocarcinoma (PDAC) is exceptionally resistant to immune checkpoint inhibition (ICI). We previously reported that elevated systemic interleukin-6 (IL-6) and increased numbers of T cells positive for circulating cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) correlate with worse overall survival in patients with PDAC. We postulated that combined blockade of IL-6 and CTLA-4 would significantly enhance anti-tumor immune responses to PDAC. Dual blockade of IL-6 and CTLA-4 in immune competent mice bearing subcutaneously injected pancreatic tumors significantly inhibited tumor growth, accompanied by overwhelming T cell infiltration. Therapeutic efficacy was confirmed in an orthotopic murine model of pancreatic cancer and T cell depletion studies unveiled a unique dependence on CD4+ T cells for anti-tumor activity of dual IL-6 and CTLA-4 blockade. In vitro studies utilizing T cells from a TRP-1 transgenic mouse as an antigen-specific model system demonstrate this combination therapy elicits increased IFN-{gamma} production by activated CD4+ T cells. Additionally, IFN-{gamma} stimulation of pancreatic tumor cells in vitro profoundly increased tumor cell production of CXCR3 specific chemokines (CXCL10 and CXCL9). Further studies blocking CXCR3 in the presence of combined IL-6 and CTLA-4 blockade prevented orthotopic tumor regression, demonstrating a dependence on the CXCR3 axis for anti-tumor efficacy. We also found combination therapy increased intratumoral CD4+ T cells and elicited systemic changes in T-helper subsets. These data represent the first report of IL-6 and CTLA-4 blockade as a means to regress pancreatic tumors with defined operative mechanisms of efficacy. Given these results, this therapeutic combination has potential for immediate clinical translation. One Sentence SummaryBlockade of interleukin-6 in pancreatic cancer enhances CTLA-4 immune checkpoint inhibition to regress tumors in a CD4+ T cell and CXCR3-dependent manner.

cancer biology↗