José R. Conejo-Garcia, M.D., Ph.D.
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. Conejo-Garcia has contributed to most significant advances in the understating of the recruitment, regulation and functions of immunosuppressive cells in the microenvironment of gynecologic malignancies made in recent years. Novel immunotherapeutic interventions based on this mechanistic insight have been designed are being tested in preclinical systems. Some major interests in the lab include:
1. Understanding the initiation and evolution of the ovarian carcinoma microenvironment
We are currently elucidating the nature of the tumor-specific antigens that trigger the initial recognition of nascent ovarian tumors, and how these responses evolve from initiation to terminal disease. Ovarian and basal breast cancers are, as supported by multiple independent studies, p53-driven immunogenic diseases where the density and/or the pattern of infiltration of T cells are indisputably associated with better outcomes. However, an emerging paradox in the field is that these malignancies accumulate very few missense mutations, compared to other tumors such as melanoma, where p53 is rarely mutated. In fact, recent evidence derived from the analysis of TCGA datasets indicates that, unlike in tumors such as colo-rectal cancer or glioblastoma, there is no association between predicted neo-antigens and markers of lymphocyte-mediated cytolysis in ovarian cancer, with limited exceptions. And yet, ovarian carcinoma is an immunogenic disease.
The immunobiology of ovarian cancer therefore appears to escape the “immunoediting” framework supported by models of carcinogen-induced sarcomas. We are dissecting what antigens elicit the primordial T cell response in ovarian carcinoma, using inducible p53-driven orthotopic ovarian tumors generated in the lab, and how these responses evolve as immunosuppression is orchestrated.
2. Epigenetic programs driving immunoenvironment of gynecologic malignancies
We are also 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 genetic and epigenetic programs 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/epigenetic networks in the acquisition of an immunosuppressive phenotype by VLCs (and regulatory DCs in general) at tumor locations.
[In the figure, CD11c depletion.]
3. Epigenetics of T cell unresponsiveness in the tumor microenvironment
Another area of interest in collaboration with Wistar researchers is identifying inter- or intra-chromosomal interactions in tumor microenvironmental T cells and elucidating how they contribute to explain their unresponsive phenotype. This includes defining the 3D structure of the genome of tumor-reactive T cells paralyzed in the tumor microenvironment in response to multiple immunosuppressive networks.
The lab is also elucidating how direct DNA de-methylation at tumor locations alters the activity of anti-tumor T cells, and how genetic variation in critical mediators of this process influences the patient’s outcome.
We are finally pursuing transcriptional programs driving anergy, exhaustion and quiescence
4. Genetic determinants of protective immunity and tumor-promoting inflammation
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.