PRESIDENT'S DISTINGUISHED LECTURER II
Jennifer Richer, PhD
Professor and Co-Leader of the University of Colorado Tumor Host Interactions Program
Denver, CO, USA
Friday, March 24, 2023
8:10 a.m. - 9:00 a.m.
Lecture Description
Breast and ovarian cancers co-opt mechanisms of immune suppression used during pregnancy
MM Williams, MM, Spoelstra, NS, Christenson, JL, Kuo L, Crump, LS, and JK Richer
Normal processes during embryonic development that support fetal tolerance can be co-opted by cancer cells to promote immune-suppression and metastatic spread. We find that aggressive breast and ovarian cancers produce similar factors to those made by syncytiotrophoblast to suppress the maternal immune system and ensure fetal tolerance during pregnancy.
Common mechanisms control both normal and oncogenic epithelial to mesenchymal transition (EMT). Normal epithelial cells express high levels of the microRNA 200 family, which serves to target and represses genes that should not be expressed as protein in well-differentiated epithelial cells. However, highly aggressive carcinomas often lose expression of this miRNA family and as a consequence, mesenchymal or neuronal genes and proteins can be aberrantly expressed as part of an oncogenic EMT. Restoration of miR-200c to dedifferentiated carcinoma cells not only reduced the classic EMT signature, but also numerous genes that encode immune-suppressive factors, such as CD274/CD273, that encodes Programmed Cell Death 1 Ligand 1 (PD-L1), and Growth/Differentiation Factor 15 (GDF-15) also known as Placental Bone Morphogenetic Protein. In addition, enzymes such as Tryptophan-2,3-dioxygenase (TDO2) and Heme Oxygenase (HMOX1) that produce immunosuppressive metabolites were reduced. Follow-up analyses demonstrated that these genes are directly targeted and reduced by miR-200c. TDO2, a rate-limiting enzyme in the tryptophan catabolism pathway, is expressed in aggressive breast and ovarian cancers in anchorage-independent growth conditions. Decreased levels of TDO2 resulted in tumor cells producing less of the immunosuppressive metabolite kynurenine, which reduces viability of cytotoxic T cells, but expands T regulatory cells. Likewise, heme oxygenase 1, HO-1 (encoded by HMOX1), which also produces catabolites with immune-suppressive properties, is also directly targeted and decreased. Thus miR-200c restoration revealed specific targetable immune-modulatory mechanisms utilized by aggressive cancers. Interestingly, many of these same factors are produced by trophoblasts and the placenta to support maternal immune suppression during pregnancy.
Cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) were also increased upon restoration of microRNA-200c to drive mouse mammary carcinoma and human triple negative breast cancer cells toward a more epithelial state. This miR-200c-induced cytokine milieu supported M1-like antitumor macrophage polarization in mouse mammary tumors and correlates with increased M1 macrophage polarization and better overall survival in triple-negative breast cancer patients. Our findings demonstrate that immune suppressive factors are elevated in aggressive, dedifferentiated carcinoma cells, while immunogenic cytokines such as GM-CSF are suppressed. In summary, mechanisms of immune suppression utilized by cancer cells to escape immune recognition are also utilized by syncytiotrophoblast to suppress the maternal immune system.
Learning objectives:
- Learn how common factors control immune-suppression during pregnancy and cancer
- Understand mechanisms that control normal and oncogenic epithelial to mesenchymal transition during development and cancer respectively.
- Discuss how metabolic enzymes can generate immune-suppressive metabolites.
About Dr. Richer
Dr. Jennifer Richer, Professor with tenure, Department of Pathology, University of Colorado Anschutz Medical Campus, has studied steroid hormone receptor action in breast and gynecologic cancers for over 25 years. Translational studies from her lab led to two recently completed clinical trials targeting androgen receptors in primary and metastatic breast cancer with de novo or acquired resistance to ER-directed endocrine therapy. The Richer lab also discovered a mechanism by which carcinomas can co-opt use of immune-suppressive factors typically made by trophoblasts to ensure fetal tolerance during pregnancy.
Richer has held leadership positions at the national and institutional level, including in the University of Colorado Cancer Center as Co-Leader of the Tumor Host Interactions Program brings together faculty studying systemic host conditions such as puberty, pregnancy, and obesity other conditions that affect tumor therapeutic response or progression. Her national service includes 5 years as a standing member of the NIH Tumor Cell Biology study section and numerous other grant review panels. She was the Basic Science Chair for The Endocrine Society Annual Meeting 2021 and Co-chair of the 2016 Keystone Symposium on Nuclear Hormone Receptors. She is an associate editor for Endocrinology and Breast Cancer Research.
With a passion for supporting the next generation of scientists, Richer has served as principal investigator of the University of Colorado’s American Cancer Society Institutional Research Grant for junior faculty pilot projects and the Diversity in Cancer Research Summer Fellowship. Richer received the Dean’s Mentoring Award and the NIH Broadening Experiences in Scientific Training (BEST) Faculty Sponsor Award from the Graduate School in 2015. Her trainees have obtained numerous fellowships including NIH F31s, F32, F99/K00s, K99/R00, Department of Defense training grants, and career development awards from private foundations. She was just named as the new Graduate School Dean of the University of Colorado Anschutz Medical Campus, a half time position so that she can keep her research program active.