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Germline Genetic Determination of Cancer Outcome
Get PDFImmunotherapy has transformed the treatment of melanoma patients. However, despite the enormous promise of immunotherapy, a major fraction of patients with advanced melanoma still succumb to this deadly disease. In addition, systemic immunotherapy can lead to relevant toxicities. Therefore, it is an unmet need to identify the factors that modulate the outcome and response to therapy of melanoma patients. One major factor accounting for individual differences in the host response to cancer is the genetic makeup of the germline. A thorough assessment of the role of germline genetics in melanoma outcome is lacking, partly because of the difficulty in assessing the vast number of genetic variants present in the human population. In this thesis, I describe the discovery of the impact of three highly prevalent variants of the Apolipoprotein E (APOE) gene on melanoma progression and outcome. Using transgenic human APOE mice, we found that mice expressing the APOE4 variant exhibit slower melanoma progression and metastasis than APOE2 mice. The impact of APOE genotype on melanoma progression was mediated by modulation of anti-melanoma immunity. APOE4 mice showed enhanced activation of anti-tumor immunity relative to APOE2 mice, and T cell depletion abrogated the impact of APOE genotype on melanoma progression. Importantly, analysis of large-scale human melanoma data validated the impact of APOE genotype on melanoma progression in humans. Amongst melanoma patients at high risk of melanoma-associated death, carriers of the APOE2 variant showed worse survival outcomes relative to APOE3 homozygotes and APOE4 carriers in two independent studies. APOE genotype also impacted melanoma outcome in the context of anti-PD1 immunotherapy in both mice and humans. Additionally, APOE4 mice derived robust benefit of pharmacologic activation of liver-X-receptors, a class of transcription factors inducing APOE expression. In contrast, APOE2 showed no treatment benefit, indicating that APOE genotype may serve as a biomarker for response to LXR-agonistic immunotherapy. Overall, our data describe the first example of highly common germline variants that modulate the outcome of a common cancer type. These findings suggest APOE to be a potential biomarker for outcome and therapy response in melanoma. More generally, our findings suggest that common variants of the germline genetic makeup substantially modulate cancer outcome and will likely be a cornerstone of precision cancer management
Expression of DEC-205 in Different Tissues
No full textSlide 4-6: Expression of DEC-205 in different tissueshttps://digitalcommons.rockefeller.edu/endocytosis/1005/thumbnail.jp
CD 16: DEC Tail Fusion Receptor
No full textSlide 4:3: CD 16: DEC Tail Fusion Receptorhttps://digitalcommons.rockefeller.edu/endocytosis/1002/thumbnail.jp
Targeting of α-DEC Antibodies
No full textSlide 4-14: Targeting of α-DEC Antibodies in situ to DCs in the T cell area in the steady statehttps://digitalcommons.rockefeller.edu/endocytosis/1013/thumbnail.jp
B16 Melanoma
No full textB16 melanoma loaded with α-Galactosyl ceramide, elicit T cell-independent innate resistance to metastasishttps://digitalcommons.rockefeller.edu/nkt-cells/1008/thumbnail.jp
Effective Adaptive Immunity
No full textSlide 5-18https://digitalcommons.rockefeller.edu/nkt-cells/1017/thumbnail.jp
Several Types of Living Tumor Cells
No full textSlide 5-11https://digitalcommons.rockefeller.edu/nkt-cells/1010/thumbnail.jp
CD11c+ Dendritic Cells
No full textSlide 5-24https://digitalcommons.rockefeller.edu/nkt-cells/1023/thumbnail.jp
Genetic Functional Dissection of the Synaptic Output of a Dual-Function Integrating Neuron
Get PDFAnimals must vary their behavior in response to changes in their environment, but behavior also remains consistent over time. This thesis focuses on a single interneuron, RIM, and a single behavior, the reversal, to better understand how the circuits driving motor outputs accomplish the seemingly contradictory tasks of generating appropriate and variable behaviors. In the compact and well-defined nervous system of C. elegans, the interneuron RIM is an important part of the reversal behavior circuit that contributes to sensory integration, behavioral variability, generation of behavioral states, and learning. RIM releases both glutamate and the biogenic amine tyramine (~noradrenaline) and forms gap junctions with neurons that govern various aspects of C. elegans locomotion. RIM is the major source of tyramine in C. elegans, and this output is known to extend reversal length of spontaneous and evoked reversals and to sharpen turns during escape response. However, the roles of RIM glutamate and RIM gap junctions in organizing reversal behavior have remained nebulous. I combine cell-specific genetic manipulations, behavioral analyses, and both manipulations and observations of neural activity to dissect the diverse synaptic outputs of the interneuron RIM. I reveal a role for RIM glutamate in spontaneous reversal behavior and show that RIM glutamate and RIM tyramine differentially regulate spontaneous reversals. Through comparative analysis of the exo- and endocytosis dynamics of RIM glutamate and tyramine, I provide evidence that they released from RIM under the same conditions and with similar dynamics, and that tyramine may also be released from a distinct, slower vesicle class. I also find that both RIM chemical synapses and electrical synapses are bidirectional regulators of C. elegans locomotion, stabilizing both the forward state and reversal state. I conclude that RIM is a dual-function neuron, able to both promote and inhibit reversal behavior
Hiller, Alma E.
No full textAlma Hiller, circa 1920s
Courtesy of the Rockefeller Archive Center
Alma E. Hiller (1892-1958) was an American biochemist who joined Van Slyke\u27s laboratory in 1918, and for 30 years she contributed as a member of his team to a wide range of studies including blood gas analysis, hemoglobin preparations, blood and urine chemistry, and kidney physiology and nephritis. She also supervised the clinical chemical work in Van Slyke\u27s laboratory, which made use of specimens from the hospital.
See also Discovering a New Amino Acid: Hydroxylysinehttps://digitalcommons.rockefeller.edu/scientific-staff/1008/thumbnail.jp