The goal of my research program is to identify and target mechanisms controlling the balance between immunosuppression and protective immunity in the tumor microenvironment. My laboratory has been investigating and modulating the recruitment, regulation and functions of immunosuppressive cells in the ovarian cancer microenvironment.
In recent years, the following projects have been established and funded:
1. Vascular Leukocytes influence the tumor microenvironment.
We are particularly interested in the tolerogenic/pro-angiogenic role of Vascular Leukocytes (VLCs), a subset of CD11c+DEC205+MHC-II+ myeloid cells that acquire phenotypic markers of endothelial cells and home to perivascular locations in the solid ovarian cancer microenvironment, in both humans and mice.
Ongoing experiments are clarifying the role of individual transcription factors and genetic networks in the acquisition of an immunosuppressive phenotype by VLCs (and regulatory DCs in general) at tumor locations.
[In the figure, CD11c depletion.]
2. Eliciting therapeutic antitumor immunity by modulating immunostimulatory miRNAs.
We are modulating the expression of various miRNAs in both tumor-reactive T cells and tumor-associated VLCs. These experiments are aimed to both boost anti-tumor immunity and understand the function of individual miRNA sequences in the biology of tumor-associated leukocytes.
3. Iron nanoparticle-mediated hyperthermia for treatment of ovarian cancer.
Another growing area of interest in my laboratory is the use of nanomaterials to boost anti-tumor immunity. In collaboration with Steve Fiering and other researchers at Dartmouth College, we are taking advantage of the enhanced endocytic capacity of tumor-associated VLCs and their spontaneous homing to solid tumor sites to concentrate magnetic nanoparticles in metastatic tumor masses. We are currently optimizing the magnetic excitation of these particles to induce selective hyperthermia-mediated killing of tumor cells. We are also very interested in the immunogenic effects of this approach and how it can synergize with standard treatments.
4. Understanding the initiation and evolution of the ovarian cancer microenvironment.
A final area of interest recently funded is focused on understanding of the bi-directional interaction between mutated tumor cells and inflammatory leukocytes during cancer initiation and neoplastic progression. We have generated an inducible genetic model of ovarian carcinoma that leads to terminal metastatic disease complete penetrance and recapitulates the inflammatory microenvironment of human tumors in previously healthy mice in a C57BL6 background. We are currently defining how different combinations of initial mutations impact the immunobiology of ovarian cancer. We are also elucidating what determines that these tumors can progress at all, how they are kept in check for relatively long periods, and what promotes their eventual exponential growth.