Demehri Lab

Research Summary

The focus of the Demehri laboratory is to determine the role of the immune system in regulating the early stages of cancer development in order to harness its anti-tumor potential for cancer prevention and treatment. To date, several cancer immunotherapies have been developed with proven efficacy against late-stage cancers; however, the role of the immune system in preventing the early development of cancer remains uncertain. The research in the Demehri laboratory is focused on identifying the immune mechanisms that drive an immune activation sufficient to prevent cancer formation from pre-cancerous lesions. This approach raises a great opportunity to discover novel immune pathways that can be leveraged in cancer therapy and prevention.

Research Projects

The field of cancer immunology has made substantial advances in recent years by deciphering the role of the tumor infiltrating CD8+ cytotoxic T lymphocytes (CTLs) in attacking cancer cells, which have led to promising new cancer immunotherapeutics. The current immunotherapeutic approaches, however, are largely designed to boost the anti-tumor immune response that has already formed against late-stage metastatic cancers. Therefore, the current cancer immunotherapies like immune checkpoint blockade, which rely on a pre-existing CTL infiltrate in the tumor for their effects, are proven ineffective to treat cancers that frequently lack a significant anti-tumor immune infiltrate, especially during the early in-situ phases of their development. In order to expand the potential of cancer immunotherapy, our laboratory studies the pathways that lead to immune system activation against early phases of cancer development. Devising a mechanism to activate the immune system against early- stage cancers has clear immunopreventive implications by directly blocking the cancer promotion and immunotherapeutic benefits by potentiating the immunity against late disease.

To pursue this goal, the Demehri laboratory is currently focused on three areas of research:

1. Mechanisms of CD4+ T cell activation against cancer. Our laboratory has studied the mechanism of thymic stromal lymphopoietin (TSLP) in evoking tumor suppression. TSLP is an epithelial-derived cytokine that plays a central role in stimulating CD4+ T helper 2 (Th2)-mediated allergic diseases like atopic dermatitis and asthma. We have shown that high TSLP levels establish a dominant anti-tumorigenic immune environment preventing cancer promotion. Currently, our team investigates the detailed mechanism of TSLP anti-tumor function against solid cancers and examines its application for the treatment of pre- cancerous skin and breast lesions in patients.
2. Mechanisms of natural killer (NK) cell recruitment and activation against cancer. NK cells are known for their potent anti- tumor properties. However, their role in controlling the cancer development in vivo remains unclear. Our laboratory is utilizing a virally encoded ligand for NK cells to determine the combination of signals necessary to activate NK cells against early stages of carcinogenesis and to identify the mechanism of anti-tumor immunity mounted by the activated NK cells in order to block cancer promotion and progression.
3. Mechanisms of tumor promotion by the immune system. Although immune cells can mount anti-tumor immunity against cancer, they are also implicated in promoting cancer development under certain conditions. Chronic inflammation is one of the conditions that can predispose patients to cancer; however, the mechanism of such immune-mediated tumor promotion is unclear. To determine this mechanism, our laboratory studies skin and colorectal cancer development as ideal cancer models in which the spatial and temporal relationship between inflammation and cancer development can be determined with exceptional precision. We are currently investigating the immune mechanisms that promote skin cancer development in the context of chronic allergic contact dermatitis and cutaneous lupus and colorectal cancer development in the context inflammatory bowel disease.

Research Positions

Postdoctoral Research Fellow position is available for a highly motivated individual with expertise in immunology, cancer biology and genomics. Expertise in biochemical, immunological and mice experimentations are required for this position.

Interested candidates should send their information including CV and the name of 2-3 references to Dr. Shawn Demehri: sdemehri1@mgh.harvard.edu

Publications

For the full list of publications from the Demehri lab, please visit PubMed here.

Park JH, Ameri AH, Dempsey KE, Conrad DN, Kem M, Mino-Kenudson M, and Demehri S. Nuclear IL-33/SMAD signaling axis promotes cancer development in chronic inflammation. EMBO J. 2021 (in press).

Strickley JD, Messerschmidt JL, Awad ME, Li T, Hasegawa T, Ha DT, Nabeta HW, Bevins PA, Ngo KH, Asgari MM, Nazarian RM, Neel VA, Jenson AB, Joh J, and Demehri S. Immunity to commensal papillomaviruses protects against skin cancer. Nature. 2019 Nov;575(7783):519-522. PMID: 31666702.

Rosenberg AR, Tabacchi M, Ngo KH, Wallendorf M, Rosman IS, Cornelius LA, Demehri S. Skin cancer precursor immunotherapy for squamous cell carcinoma prevention. JCI Insight. 2019;4(6). Epub 2019/03/22. doi: 10.1172/jci.insight.125476.

Ameri AH, Moradi Tuchayi S, Zaalberg A, Park JH, Ngo KH, Li T, Lopez E, Colonna M, Lee RT, Mino-Kenudson M, Demehri S. IL-33/regulatory T cell axis triggers the development of a tumor-promoting immune environment in chronic inflammation. Proceedings of the National Academy of Sciences of the United States of America. 2019. Epub 2019/01/31. doi: 10.1073/pnas.1815016116. 

Zaalberg A, MoradiTuchayi S, Ameri AH, Ngo KH, Cunningham TJ, Eliane JP, Livneh M, Horn TD, Rosman IS, Musiek A, Anadkat MJ, Demehri S. Chronic inflammation promotes skin carcinogenesis in cancer-prone discoid lupus erythematosus. The Journal of investigative dermatology. 2018 Jul 17. pii: S0022-202X(18)32328-5.

Cunningham, T.J., Tabacchi, M., Eliane, J.P., Tuchayi, S.M., Manivasagam, S., Mirzaalian, H., Turkoz, A., Kopan, R., Schaffer, A., Saavedra, A.P., Wallendorf, M., Cornelius, L.A., and Demehri, S. Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy. J Clin Invest 2017; 127(1): 106-116.

Demehri, S., Cunningham, T.J., Manivasagam, S., Ngo, K.H., Moradi Tuchayi, S., Reddy, R., Meyers, M.A., DeNardo, D.G., and Yokoyama, W.M. Thymic stromal lymphopoietin blocks early stages of breast carcinogenesis. J Clin Invest 2016; 126(4): 1458-70.

Demehri, S., Turkoz, A., Manivasagam, S., Yockey, L.J., Turkoz, M., and Kopan, R. Elevated epidermal thymic stromal lymphopoietin levels establish an antitumor environment in the skin. Cancer Cell 2012; 22(4): 494-505.

Our Researchers

Shawn Demehri, M.D., Ph.D.

Associate Professor
Massachusetts General Hospital
Harvard Medical School

B.S.: Biology, Washington State University
M.D.: Washington University in St. Louis
Ph.D.: Cell and Molecular Biology, Washington University in St. Louis
Residency: Dermatology, Barnes Jewish Hospital/ Washington University
Postdoctoral Fellowship: Immunology, Washington University in St. Louis

 

Marjan Azin, M.D.

Research Fellow

M.D.: Tehran University of Medical Science (TUMS), Iran

Marjan received her medical diploma from Tehran University of Medical Science in 2015. She has directed research projects at her hospital, studying the prognostic significance of Matrix Metalloproteinase-7 (MMP-7) in colorectal cancer survival, the effect of exercise program in serum Vaspin level in diabetic patients, and studying sleep disorders in patients with neuropathic pain. At Children Medical Center, she the immune dysregulation in children with allergic skin diseases. Marjan is studying the role of alarmins in suppressing cancer development in patients with breast cancer cutaneous metastasis in the Demehri lab.

 

Scarlett (Se Yun) Cheon

Research Technician

B.A.: Wellesley College

Scarlett has recently received her B.A. degree in Biological Sciences from Wellesley College. She has previously worked in the Knoechel lab, a cancer epigenetic lab, at Dana Farber Cancer Institute/Boston Children’s Hospital and the Fusco lab at MGH/HMS. In the Fusco lab, she worked on identifying host factors that are required in interferon antiviral response post viral subversion points through in vitro and in vivo models for Dengue/Zika viruses. In the Demehri lab, Scarlett is studying the mechanism of NK and other immune cells activation in the skin.

 

Ranya Guennoun

Research Technician

B.S.: Microbiology,Oregon State University

Ranya has recently received her Bachelor of Science in Microbiology with a Chemistry minor and a Pre-Medical Option at Oregon State University. Her previous research experience has been focused on understanding the role that Vitamin D plays in the regulation of the human antimicrobial peptide Cathelicidin. She hopes to attend Medical School in the next upcoming years and pursue a career in Oncology. At the Demehri Laboratory, she is studying the role of CD4+ T-cells in regulating lung cancer development.

 

Thinh Dat (Andy) Ha

Research Technician

B.S.: Biology, Western Kentucky University
M.S.: Chemistry, Western Kentucky University

Andy received his Master of Science degree in Chemistry from Western Kentucky University studying engineered zinc finger proteins to develop new sensing technology for double-stranded DNA. He developed different non-PCR detection systems for pathogenic DNA sequence such stx2 gene encoding for shiga toxin presence in E. coli O157:H7, as well as tetracycline resistance genes for the detection of antibiotic resistant bacteria. Andy is currently conducting research on the interplay of mouse papillomavirus, host immunity and cancer under the supervision of Dr. Joongho Joh at University of Louisville James Graham Brown Cancer Center.

 

Hiroshi Higuchi, Ph.D.

Postdoctoral Fellow

B.S., M.S. & Ph.D.: Bioengineering, Nagoya University, Japan

Hiroshi received his Ph.D. in 2016 studying the role of sialic acid-binding lectin Siglecs in the inflammatory regulation in macrophages. He also worked on the analysis of macrophage function in the development of Epstein-Barr virus (EBV)-associated B-cell lymphoma as a Postdoctoral Fellow in Japan. In this study, he demonstrated the importance of extracellular vesicles as a novel communicator between tumor cells and macrophages. His current work in the Demehri Lab is focused on the innate immune function of epithelial cells in response to papillomavirus infection.

 

Mei Huang, Ph.D.

Research Fellow

B.S.: Biological Science, Anhui University, China
M.S. & Ph.D.: Cellular Biology, University of Science and Technology of China, China

Mei received her PhD degree in cellular biology from USTC. Her project was to construct a single adenoviral vector that simultaneously expressed multiple siRNA expression cassettes and inhibited the target gene expression on mouse hepatocytes by intravenous injection into mice. The target molecules are various ligands of NKG2D, which is an innate activating receptor on NK cells, γδT cells and CD8+T cells. This intervention therapy prevents natural killer cell-mediated fulminant hepatitis in mice. At the First Affiliated Hospital of USTC, she studied the mechanism of NK cell exhaustion in human hepatocellular carcinoma. Her current work in the Demehri laboratory is focused on understanding how carcinogen exposure leads to higher tumor immunogenicity besides just increasing the neoantigen load in the tumor cells.

 

Monica Jaffee

Undergraduate Student

Monica is a current undergraduate at Northeastern University pursuing a B.S. degree in Biological Sciences and a B.A. degree in Philosophy of Ethics. Her background includes lab work in biological contamination as well as in bacterial cell cultures. In the Demehri lab, Monica is studying the mechanism of NK cell effects in cancer immunology.

 

Tomonori Oka, M.D., Ph.D.

Postdoctoral Fellow

M.D.: University of Tokyo, Japan
Ph.D.: Dermatology, University of Tokyo, Japan

Tomonori received his Ph.D. degree in Dermatological sciences in 2018 studying the role of CXCL17 in psoriasis. During his clinical work as a dermatologist, he has focused on cutaneous T-cell lymphoma and atopic dermatitis. In the Demehri Lab, Tomonori is studying the mechanisms of skin cancer immunoprevention.

 

Jongho Park, Ph.D.

Postdoctoral Fellow

B.Sc.: Computer Science Engineering and Biomedical Science, Pusan National University, Pusan, Korea
M.S. & Ph.D.: Biological Science, Seoul National University, Seoul, Korea

Jongho received his Ph.D. in biological science in 2016 studying protein modifications, such as ubiquitination and SUMOylation. He demonstrated a novel post-translational modification of tumor suppressor DBC1 and p53 induced by DNA damage, which can lead to upregulation of their suppressor activity. During his work in industry, Jongho has investigated the mechanism of rare genetic diseases, such as hemophilia, for the development of new therapeutic antibodies. His current work in the Demehri laboratory is focused on molecular signaling pathway within keratinocyte that can govern skin cancer immunity.

 

Heehwa (Grace) Son, Ph.D.

Postdoctoral Fellow

B.Sc.: Biotechnology, Konkuk University, Seoul, South Korea
M.S. & Ph.D.: Molecular biology and Genetics, Pohang University of Science and Technology (POSTECH), Pohang, South Korea

Heehwa received her PhD in molecular biology and genetics in 2018 studying the roles of RNA quality controls in aging process using a model organism, C. elegans. She found that one of the RNA quality control mechanisms, nonsense-mediated mRNA decay, has protective effects against aging. She also worked on investigating the roles of chaperones in lifespan regulation. In the Demehri lab, she is working on the cellular impacts of immunotherapies on early stage epithelial cancers.

 

Kathryn Trerice

Undergraduate Student

Katie is an undergraduate at Harvard College pursing a B.S. degree in Molecular and Cellular Biology. She is working with other lab members on their research projects while expanding both her knowledge of the field and her skills. Katie has joined our efforts to understand the role of CD4+ T cells in regulating lung cancer development.

 

Maulik Vyas, Ph.D.

Postdoctoral Fellow

B.Sc. (Honors): Biomedical Science, University of Central Lancashire, UK
M.Sc.: Cancer Immunology & Biotechnology, University of Nottingham, UK
Ph.D.: Cancer Immunotherapy, University of Cologne, Germany

Maulik received his PhD in the field of Cancer Immunotherapy in 2016 where his work focused on designing and developing recombinant trispecific immunoligands (“triplebodies”) to harness NK cells against leukemia. His triplebodies showed successful retargeting of NKG2D-dependent NK cell response against primary leukemia cells in both, allogeneic and autologous settings. Significant in vivo potency of the triplebody was observed in immunodeficient (NSG) mouse model which further suggested its therapeutic potential. Maulik then worked as a postdoctoral fellow at Philipps University Marburg, Germany to study the NK cell suppression in response to soluble NKG2D-ligands or other yet unknown factors present within the ascites of ovarian cancer patients. His current work in the Demehri laboratory is focused on understanding how immune cells, in particular NK cells, regulate the early stages of cancer development.

 

Yun Xia, Ph.D.

Postdoctoral Fellow

B.Sc. Biotechnology, Anhui normal University, China
M.Sc.: Immunology, Soochow University, China
Ph.D.: Immunology, Tsinghua University, China

Yun received his PhD degree in immunology from Tsinghua University in 2020. He found that mevalonate pathway inhibitors could induce strong immune responses and were suitable for vaccine adjuvants. The adjuvanticity associated with mevalonate pathway inhibition activates multiple arms of immunity, including Th1 and cytolytic T cell responses and is thus suitable for cancer immunotherapies. This discovery presented a new approach for the development of both vaccine and cancer research. In the Demehri lab, Yun focuses on studying the role of alarmins in COVID-19 response and the role of commensal viruses in immunity at epithelial sites.

 

Martina Zoi

Research Technician

B.S. Biological Science (Degree in Progress), Northeastern University
B.S.: Medical Laboratories, University of West Attica, Athens, Greece

Martina joined Demehri lab as a student pursuing her Bachelor of Science degree in Biological science from Northeastern University. She has previously received a B.S. degree in Medical Laboratories at the University of West Attica. Though her background is in diagnostic laboratories, she hopes to gain research experience and advance her knowledge and skills to laboratory studies that will follow while assisting research fellows with their projects by conducting research experiments. She is interested in studying genetics and its role in breast cancer in its early development.

 

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Demehri Lab Alumni

• Amir Ameri, M.D.
• Mary Awad, M.D.
• Margherita Boieri, Ph.D.
• Mark Bunting, Ph.D.
• Danielle Conrad
• Trevor Cunningham
• Kaitlin Dempsey
• Roy Feng, M.D.
• Aeden Ghebreselassie, MSN, NP-C
• Tatsuya Hasegawa, Ph.D.
• Sanne Kroon
• Kaiwen Li, M.D.
• Tiancheng Li, M.D.
• Elena Lopez
• Jonathan Messerschmidt
• Sara Moradi Tuchayi, M.D., M.P.H.
• Kenneth Ngo
• Marta Requesens Rueda
• Erik Schiferle
• Bo Wang, Ph.D.
• Anniek Zaalberg
• Anna Zemel, Ph.D.