Schematic representation of the inflammatory microenvironment of solid ovarian carcinomas
The primary goal of Conejo-Garcia research program is to identify and target mechanisms controlling the balance between immunosuppression and protective immunity in the tumor microenvironment. The Conejo-Garcia laboratory has been contributing to the understating of the recruitment, regulation and functions of immunosuppressive cells in the microenvironment of gynecologic malignancies. Novel immunotherapeutic interventions based on this mechanistic insight have been designed are being tested in preclinical systems.
In recent years, the following projects have been established and funded by the NCI:
1. Vascular Leukocytes influence the tumor microenvironment
We are particularly interested in a subset of immunosuppressive/proangiogenic leukocytes that phenotypically resemble dendritic cells and distinctively accumulate in human and mouse ovarian cancer, termed by us Vascular Leukocytes (VLCs). We are elucidating the molecular factors that ultimately drive the tolerogenic activity and selective accumulation of VLCs (and regulatory DCs in general) at tumor locations. The lab has identified that Special AT-rich sequence binding protein 1 (Satb1), a master programmer controlling genome-wide transcriptional
programs, is overexpressed in the nuclei of tumor VLCs, in both mice and humans. Importantly, in vivo Satb1 silencing results the abrogation of the immunosuppressive phenotype of VLCs. We are working to define Satb1 – a global organizer of genome-wide transcriptional programs - as the master regulator ultimately driving the immunosuppressive activity and preferential accumulation of VLCs in ovarian cancer, which will be applicable to regulatory DCs in other lethal tumors and has obvious implications for development of improved immunotherapies.
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. Genetic determinants of tumor immunosurveillance
At least 30% of individuals in the general population are carriers of a limited set of polymorphisms in pattern recognition receptors (PRRs) genes. Although these polymorphisms are compatible with a healthy life, they are functionally relevant because the carriers’ susceptibility to develop certain infectious and/or autoimmune diseases is altered. Still, how mechanisms of tumor immunosurveillance are affected in these individuals remains completely unknown.
The lab is investigating how frequent genetic alterations in PRRs and related molecules modify mechanism of tumor immunosurveillance through dissimilar interactions with the microbiota, which may lead to different immune responses against primordial tumor lesions, both in terms of quality and magnitude. We are also elucidating how tumor-bearing hosts carrying frequent polymorphisms in PRR molecules orchestrate different anti-tumor immune microenvironments that could make them more responsive (or resistant) to specific immunotherapeutic interventions.
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.