The Role of NOTCH3 in Determining Adipose Derived Stem Cell Fate

Jacob Cambre, Hannah Logan, Avery Bryan, and Demi Sandel are undergraduate students in Biology at Louisiana Tech University. Mengcheng Liu and Ngozi Ogbonnaya are graduate students in Biology at Louisiana Tech University. Jamie Newman is a Professor in Biological Sciences at Louisiana Tech University

Commensal Microbiota Promote Lung Cancer Development via γδ T Cells

Lung cancer is closely associated with chronic inflammation, but the causes of inflammation and the specific immune mediators have not been fully elucidated. The lung is a mucosal tissue colonized by a diverse bacterial community, and pulmonary infections commonly present in lung cancer patients are linked to clinical outcomes. Here, we provide evidence that local microbiota provoke inflammation associated with lung adenocarcinoma by activating lung-resident γδ T cells. Germ-free or antibiotic-treated mice were significantly protected from lung cancer development induced by Kras mutation and p53 loss. Mechanistically, commensal bacteria stimulated Myd88-dependent IL-1β and IL-23 production from myeloid cells, inducing proliferation and activation of Vγ6 + Vδ1 + γδ T cells that produced IL-17 and other effector molecules to promote inflammation and tumor cell proliferation. Our findings clearly link local microbiota-immune crosstalk to lung tumor development and thereby define key cellular and molecular mediators that may serve as effective targets in lung cancer intervention. Lung cancer development is associated with increased bacterial burden and altered bacterial composition in the lung. Depletion of microbiota or blockade of the downstream cellular or molecular immune mediators significantly suppress lung tumor growth.National Cancer Institute (U.S.) ( K99 Award CA226400)United States. Department of Defense. Lung Cancer Research Program ( Concept Award W81XWH-15–1–0623)National Cancer Institute (U.S.) ( R01 Grant CA185020)National Cancer Institute (U.S.) (Core Grant P30-CA14051)National Cancer Institute (U.S.) (Grant P30-ES002109

Rebalancing Protein Homeostasis Enhances Tumor Antigen Presentation

Purpose: Despite the accumulation of extensive genomic alterations, many cancers fail to be recognized as "foreign" and escape destruction by the host immune system. Immunotherapies designed to address this problem by directly stimulating immune effector cells have led to some remarkable clinical outcomes, but unfortunately, most cancers fail to respond, prompting the need to identify additional immunomodulatory treatment options. Experimental Design: We elucidated the effect of a novel treatment paradigm using sustained, low-dose HSP90 inhibition in vitro and in syngeneic mouse models using genetic and pharmacologic tools. Profiling of treatment-associated tumor cell antigens was performed using immunoprecipitation followed by peptide mass spectrometry. Results: We show that sustained, low-level inhibition of HSP90 both amplifies and diversifies the antigenic repertoire presented by tumor cells onMHC-Imolecules through an IFNgindependent mechanism. In stark contrast, we find that acute, high-dose exposure to HSP90 inhibitors, the only approach studied in the clinic to date, is broadly immunosuppressive in cell culture and in patients with cancer. In mice, chronic nonheat shock-inducing HSP90 inhibition slowed progression of coloncancerimplants, but only in syngeneic animals with intact immune function. Addition of a single dose of nonspecific immune adjuvant to the regimen dramatically increased efficacy, curing a subset of mice receiving combination therapy. Conclusions: These highly translatable observations support reconsideration of the most effective strategy for targeting HSP90 to treat cancers and suggest a practical approach to repurposing current orally bioavailable HSP90 inhibitors as a new immunotherapeutic strategy.National Institutes of Health (Grant P30-CA14051