Professor of Biology
KI Research Areas of Focus:
Professor of Biology
KI Research Areas of Focus:
"We seek to understand the cellular and molecular mechanisms underlying the development and function of the immune system. Our goal is that the knowledge we gain will lead to more effective immunotherapies for cancer and other diseases. Our laboratory studies cellular and molecular mechanisms underlying the interactions between immune cells and cancer and pathogens. We are actively developing engineered natural killer cells for cancer immunotherapy, reprogramming macrophages for treating cancer and metabolic diseases, and developing a mRNA-based vaccine platform for application in SARS CoV-2 and dengue vaccine development.”
Dr. Chen received a BS degree from Wuhan University in China and a PhD in Genetics from Stanford University. He was a post-doctoral fellow and then an instructor at Harvard Medical School before he joined the MIT faculty in the Department of Biology.
Natural Killer (NK) cells and CD8+ cytotoxic T cells are two types of immune cells that can kill target cells through similar cytotoxic mechanisms. With the remarkable success of chimeric antigen receptor (CAR)-engineered T (CAR-T) cells for treating hematological malignancies, there is a rapid growing interest in developing CAR-engineered NK (CAR-NK) cells for cancer therapy. Compared to CAR-T cells, CAR-NK cells could offer some significant advantages, including (Xie et al., accepted): (1) better safety, such as a lack or minimal cytokine release syndrome and neurotoxicity in autologous setting and graft-versus-host disease in allogenic setting, (2) multiple mechanisms for activating cytotoxic activity, and (3) high feasibility for ‘off-the-shelf’ manufacturing. We have developed tumor-specific CAR for acute myeloid leukemia (AML) (Xie et al., accepted) and other tumors. In collaboration with Professor Rizwan Romee at Dana-Farber Cancer Institute, we are developing CAR-NK cells using cytokine-induced memory-like NK cells for AML (Romee et al., 2016), evaluating their efficacy in preclinical models and in humans. Moving forward, we are developing the next generation of CAR-NK cells to target diverse antigens, enhance proliferation and persistence in vivo, increase infiltration into solid tumors, overcome resistant tumor microenvironment, and ultimately achieve an effective anti-tumor response in patients.
Macrophages are a key class of phagocytic cells that readily engulf and degrade dying/dead cells and invading bacteria and viruses. As such, macrophages play an essential role in development, tissue homeostasis and repair, and immunity. In mammals, the first wave of macrophages is generated from the yolk sac and gives rise to macrophages in the central nervous system, i.e., microglia. The second wave of macrophages is generated from fetal liver and give rise to alveolar macrophages in the lung and Kupffer cells in the liver among others. After birth, macrophages are generated from the bone marrow where hematopoietic stem cells give rise to monocytes, which differentiate into tissue resident macrophages upon migration from blood into specific tissues. A remarkable feature of macrophages is their plasticity: the ability to respond to local stimuli to acquire different phenotypes and functions so as to respond to changing physiological needs. For example, macrophages can eliminate antibody-bound tumor cells through Fc receptor-mediated phagocytosis (antibody-dependent cellular phagocytosis or ADCP). However, once adapted to the tumor microenvironment, the tumor-associated macrophages (TAM) suppress anti-tumor immune responses and promote tumor growth and metastasis. To elucidate the molecular mechanisms underlying macrophage diversity and plasticity, we have identified key transcription factors that confer macrophage identity in different tissues (Hu et al, 2019). We have identified small molecule compounds that can re-program macrophage phenotype and function (Hu et al, submitted). We have studied macrophages in cancer and metabolic diseases (Pallasch et al., 2014; Roghanian et al., 2019; Li et al., 2020). Moving forward, we are interested in elucidating the mechanisms by which macrophages can be reprogrammed for disease intervention, such as cancer, metabolic diseases, and infectious diseases.
Infectious diseases are still the major challenge to human health on the global scale, inflicting enormous suffering and economic loss, as exemplified by coronavirus disease-19 (COVID-19). Like other major infectious diseases in the human history, the cost-effective and sustainable control of major infectious diseases will depend on effective vaccines. To develop an effective vaccine, it is critical to identify immunogens and protection correlates, which requires thorough understanding of host and pathogen interaction and disease pathogenesis. As part of the Singapore-MIT Alliance for Research and Technology (SMART), we have identified cellular and molecular mechanisms by which dengue virus and malaria parasites interact and evade host immune system (Chen et al., 2014; Ye et al 2019). These studies have identified possible parasite molecules for vaccine development. We have identified adjuvants for augmenting neutralizing antibody responses for dengue virus (Bidet et al 2019) and developed immunization strategies for inducing stronger and more balanced immune responses against all four serotypes of dengue virus (Hou et al., 2019). Moving forward, we continue to elucidate molecular mechanisms underlying malaria parasite-host interactions. We are also developing an mRNA-based vaccine platform that is streamlined and validated in i) antigen identification and design, ii) targeted delivery of vaccine mRNA into the dendritic cells (DCs) for inducing potent immune responses, and iii) selection of adjuvants for enhanced neutralizing antibody response. This platform will be used for vaccine development for SARS-CoV-2 and dengue viruses.
Xie G, Dong H, Liang Y, Ham JD, Romee R, Chen J. CAR-nK cells: a promising cellular immunotherapy for cancer. EBioMedicine, accepted.
Xie G, Ivica N, Jia B, LI Y, Dong H, Liang Y, Brown D, Romee R, Chen J. Engineered CAR-T cells targeting a neoepitope derived from intracellular NPM1c exhibit potent activity and specificity against human acute myeloid leukemia. Nature Biomedical Engineering, accepted.
Romee R, Rosario M, Berrien-Elliott MM, Wagner JA, Jewell BA, Schappe T, Leong JW, Abdel-Latif S, Schneider SE, Willey S, Neal CC, Yu L, Oh ST, Lee YS, Mulder A, Claas F, Cooper MA, Fehniger TA. (2016) Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci Transl Med. 8:357ra123. PMID: 27655849.
Hu G, Dong T, Wang S, Jing H, Chen J. (2019) Vitamin D3-vitamin D receptor axis suppresses pulmonary emphysema by maintaining alveolar macrophage homeostasis and function. EBioMedicine, pii: S2352-3964(19)30420-7. PMID: 31278070.
Hu G, Su Y, Kang B, Fan Z, Dong T, Brown D, Cheah J, Wittrup KD, Chen J. High throughput phenotypic screen and transcriptional analysis identify new compounds, targets and pathways for macrophage reprogramming. Revised for Nature Communications.
Pallasch CP, Leskov I, Braun CJ, Vorholt D, Drake A, Soto-Feliciano YM, Bent EH, Schwamb J, Iliopoulou B, Kutsch N, van Rooijen N, Frenzel LP, Wendtner CM, Heukamp L, Kreuzer KA, Hallek M, Chen J, Hemann MT. (2014) Sensitizing protective tumor microenvironments to antibody-mediated therapy. Cell, 156:590-602. PMID: 24485462.
Roghanian A, Hu G, Fraser C, Singh M, Foxall RB, Meyer MJ, Lees E, Huet H, Gleenie MJ, Beers SA, Lim SH, Ashton-Key M, Thirdborough SM, Cragg MS, Chen J. (2019) Cyclophosphamide enhances cancer antibody immunotherapy in the resistant bone marrow niche by modulating macrophage FcgR expression. Cancer Immunol Res. 7:1876-1890. PMID: 31451483.
Li Y, Ivica NA, Dong T, Kleyman M, Hu G, Papageorgiou DP, He Y, Chen W, Sullivan LB, Del Rosario A, Hammond PT, Vander Heiden MG, Chen J. MFSD7C switches mitochondrial ATP synthesis to thermogenesis in response to heme. Nature Communications, accepted.
Chen Q, Amaladoss A, Ye W, Liu M, Dummler S, Kong F, Wong LH, Loo HL, Loh E, Tan SQ, Tan TC, Chang KTE, Dao M, Suresh S, Preiser PR, Chen J. (2014) Natural killer cells control Plasmodium falciparum infection by eliminating infected red blood cells. Proc Natl Acad Sci USA, 111:1479-84. PMID: 24474774.
Ye W, Chew M, Hou J, Lai F, Leopold SJ, Loo HL, Ghose A, Dutta AK, Chen Q, Ooi EE, White NJ, Dondorp AM, Preiser P, Chen J. (2018) Microvesicles from malaria-infected red blood cells activate natural killer cells via MDA5 pathway. PloS Pathogen, 14:e1007298. PMID: 30286211.
Bidet K, Collins CW, Ho V, Choy MM, Wong LH, Naim ANM, Lee YH, Florez de Sessions P, Hibberd ML, Fink K, Ooi EE, Chen J. (2019) Mimicking immune signatures of flavivirus infection with targeted adjuvants improves dengue subunit vaccine immunogenicity. NPJ Vaccines, 4:27. Doi: 10.1038/s4154`-0`9-0``9-3. PMID: 31285858.
Hou J, Shrivastava S, Loo HL, Wong LH, Ooi EE, Chen J. (2020) Sequential immunization induces strong and broad immunities against all four serotypes of dengue viruses. NPJ Vaccines, 5:68. doi: 10.1038/s41541-020-00216-0. PMID:32728482.