Adrian Erlebacher, MD, PhD

Department of Laboratory Medicine
+1 415 502-3583

Work in the Erlebacher laboratory lies at the intersection of immunology and developmental biology.  Most generally, we are interested in how the developmental properties of a tissue influence its ability to mount immune responses, and, conversely, how cells of the immune system influence tissue development and remodeling.  The main platform for our research is the mouse uterus.  This organ is not only amendable to extensive experimental manipulation, but its ability to accommodate the presence of immunologically foreign tissues during pregnancy (i.e. the fetus and placenta) provides a striking example of how the anatomical organization and developmental plasticity of a tissue determine its immunological properties.  The immunological protection afforded the fetus and placenta by the uterus is obviously critical to reproductive success, and understanding how this process breaks down has implications for clinical disorders of pregnancy.  We are also interested in how the uterine adaptations to pregnancy find parallels in the tumor microenvironment that facilitate tumor cell escape from immune-mediated destruction.  Lastly, using mouse models of uterine cancer, we are studying how nascent tumors are first detected by the immune system and how the circumstances of such detection influence tumor initiation and progression. Our recent work in this area has focused on the unexpected capacity of neutrophils, recruited as part the tumor’s early and innate response to hypoxia, to directly oppose uterine carcinogenesis independently of T cell immunity.

Current Projects

Mechanisms of “fetomaternal tolerance” and the immunology of the maternal-fetal interface.  The mystery of how the fetus avoids rejection by the maternal immune system has fascinated both reproductive biologists and immunologists alike for over 60 years. Using mice as a model organism, we have identified several major mechanisms of fetomaternal tolerance.  These include restrictions on dendritic cell trafficking from the pregnant uterus, limitations on the number of dendritic cells and macrophages that abut the placenta, and the shedding of non-immunogenic placental debris into maternal blood.  We are now studying these mechanisms in greater detail with the expectation that their dysregulation might cause aberrant T cell responses to the fetus and placenta with the potential consequence of pregnancy complications such as intrauterine growth restriction and spontaneous abortion.

Epigenetic regulation of the decidual stromal cell inflammatory response.  An additional mechanism of fetomaternal tolerance discovered by our laboratory is one that prevents activated T cells from attacking the fetus and placenta.  Specifically, we found that activated, effector T cells are unable to accumulate within the decidua, the specialized uterine stromal tissue that encases the conceptus, because decidual stromal cells fail to transcriptionally induce key T cell-attracting chemokines in response to inflammatory stimuli. We also found that this failure is due to the epigenetic silencing of the chemokine genes, in turn associated with promoter accrual of the repressive H3K27me3 histone mark. In addition to providing a major explanation for why the fetus is not rejected, this discovery demonstrates that the inflammatory response of tissue stromal cells is subject to epigenetic regulation.  It therefore implicates this mode of regulation in a wide variety of immunological phenomena. Thus, two major goals of the lab are to 1) delineate the exact molecular pathways that induce the silencing program in decidual stromal cells and 2) to determine the extent to which analogous pathways are operational in physiological and pathophysiological settings outside the context of pregnancy.  We also determining whether the epigenetic silencing of inflammatory target genes in decidual stromal cells is a feature of human pregnancy, and whether dysregulation of this pathway contributes to human pregnancy complications in particular preterm labor. 

Inflammation and immunity in the crucible of premalignancy.  A new research area in the lab is tumor immunology with a major focus on endometrial cancer, the most common gynecological malignancy.  Capitalizing on the strengths of our mouse models of the disease, we are dissecting the immune regulatory circuitry of the premalignant tumor microenvironment and identify the earliest events that induce inflammation during premalignancy.  These events are likely to have a major impact upon tumor initiation and progression.  Our major focus is the interaction between the nascent cancer and neutrophils. We are studying how neutrophils detect nascent endometrial tumors, how their pro-inflammatory products influence dendritic cell behavior during premalignancy, and how ensuing downstream effects on TH1 and TH17 priming to tumor antigens contribute to carcinogenesis.

Primary Thematic Area: 
Secondary Thematic Area: 
Cancer Biology & Cell Signaling
Research Summary: 
Immunology of pregnancy and uterine cancer

Limited Colonization Undermined by Inadequate Early Immune Responses Define the Dynamics of Decidual Listeriosis.

Infection and immunity

Rizzuto G, Tagliani E, Manandhar P, Erlebacher A, Bakardjiev AI

Neutrophils Oppose Uterine Epithelial Carcinogenesis via Debridement of Hypoxic Tumor Cells.

Cancer cell

Blaisdell A, Crequer A, Columbus D, Daikoku T, Mittal K, Dey SK, Erlebacher A

Immune mechanisms at the maternal-fetal interface: perspectives and challenges.

Nature immunology

PrabhuDas M, Bonney E, Caron K, Dey S, Erlebacher A, Fazleabas A, Fisher S, Golos T, Matzuk M, McCune JM, Mor G, Schulz L, Soares M, Spencer T, Strominger J, Way SS, Yoshinaga K

T cell behavior at the maternal-fetal interface.

The International journal of developmental biology

Nancy P, Erlebacher A