David H. Sherr, PhD

Biography

Since 1993, Dr. Sherr’s laboratory has conducted research on how common environmental pollutants, such as dioxins, polycyclic aromatic hydrocarbons (PAHs) and PCBs, suppress the immune system and induce cancer. This work has focused on molecular signals initiated by the aryl hydrocarbon receptor (AhR), a cell protein that famously is activated by a variety of common environmental chemicals. Reasoning that evolution did not select out the AhR to recognize human pollution, the Sherr lab began using environmental chemicals that activate the AhR to learn what the true function of this curious protein is. The Sherr lab was the first to demonstrate dramatically high levels of the AhR in breast cancer, an observation that would eventually be extended to cancers of the oral cavity, brain, and lung. The lab showed that, while the AhR in these cancers could be hyper-activated with environmental chemicals, the receptor was already in the “on” position, even in the absence of such chemicals. Furthermore, the Sherr lab determined that this chronic on signal was mediated at least by production of endogenous AhR activators (agonists) produced in excessive levels by malignant cells themselves. Using novel AhR inhibitors that the laboratory developed, and state-of-the-art molecular technologies including CRISPR/Cas9 gene editing, the lab demonstrated that pre-cancers and cancers were exploiting this receptor/signaling protein to up-regulate expression of genes that drive cancer invasion, metastasis, and longevity and, in doing so, enhance the production of “cancer stem cells”, a small subset of the tumor capable of withstanding chemo- and radiation therapy.

Again returning to the biologic effects of environmental chemicals, the Sherr lab then began to investigate why environmental chemicals tend to be immunosuppressive, an effect of exposure to these chemicals known to toxicologists for many years. Again, using these chemicals as probes of AhR function in biologic systems, the lab demonstrated that the AhR suppresses otherwise effective cancer-specific immune responses through the up-regulation of “immune checkpoints”, molecules that shut the immune system off. The evolving ability to inhibit these immune checkpoints with specific immune checkpoint inhibitors (PD-L1-targeted drugs) is driving the current excitement around cancer immunotherapy. That environmental chemicals increase immunosuppression through up-regulation of these immune checkpoints not only explains why environmental chemicals suppress immunity (they activate the AhR in suppressive cells of the immune system), but also suggests that some environmental chemicals deliver a double hit, first by pushing benign cells towards becoming aggressive malignancies and then through inhibition of the one biologic system capable of defending against all forms of cancers, i.e., the immune system.

While the Sherr laboratory has historically been oriented towards understanding the biologic effects of environmental chemicals to prevent cancer and to understand the basic molecular mechanisms behind cancer aggression and immunosuppression, it has most recently begun investigating how to detect the changes in cells that precede cancer formation and how to intercept cancer at these inflection points before it develops. To this end, the laboratory is now exploiting its proprietary AhR inhibitors and advanced gene editing techniques to boost anti-cancer immunity and to block transformation of benign cells into malignant cells. The lab is currently funded by grants from the NIH, The Find The Cause Breast Cancer Foundation (https://findthecausebcf.org/)(a private foundation dedicated to finding the causes of cancer and strategies to prevent cancer), and the Hahnemann Foundation.

Dr. Sherr came to BUSPH from the faculty of Harvard Medical School, where he had earlier been a postdoctoral fellow with Martin Dorf in the department of Nobel Laureate Baruj Benacerraf. His research has been supported continually by the NIH through the R01, P01, and/or P42 mechanisms since 1987. He was the founding Director of the BU Flow Cytometry Core, a former Director of the BU Immunology Training Program, and a former Director of the NIH-funded Boston University Superfund Research Program. He is currently a Co-director of the Cancer Interception Group in the BU-BMC Cancer Center and is the Director of the Find The Cause Breast Cancer Foundation Research Consortium (https://findthecausebcf.org/ftc-research-consortium). He has trained 13 undergraduate students, four Masters students, 14 Ph.D. or M.D./Ph.D. students and 24 Postdoctoral Fellows and has won the BU School of Public Health Excellence in Teaching award three times and has been nominated for the Boston University-wide Educator of the Year award 4 times.