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Research at Mass General
Nir Hacohen, PhDDirector, MGH Center for Cancer ImmunotherapyCenter for Cancer Research
Associate Professor of MedicineHarvard Medical School
Senior MemberBroad Institute
The Hacohen lab consists of immunologists, geneticists, biochemists, technologists and computational biologists working together to develop new and unbiased strategies to understand basic immune processes and immune-mediated diseases, with an emphasis on the innate immune system. We address three key questions in immunology: (1) how are immune responses against cancer initiated, maintained and evaded? (2) what are the immune circuits that sense and control pathogens, such as viruses and bacteria? (3) how does immunity against the body develop, in particular, in patients with autoimmune lupus disease. In addition to discovering and studying specific molecular and cellular mechanisms, we also address how and why the immune response (to tumors, pathogens or self) varies so dramatically across individuals. Finally, we are adapting our unbiased analytical strategies into real-world therapeutics, having initiated clinical trials (with our collaborator Dr. Catherine Wu) in which patients are vaccinated against their own tumors with a fully personalized vaccine that is designed based on a computational analysis of their personal tumor genome.
* PhD Candidates
Initiators, resistors and targets of tumor immunity
While cancer immunology has been deeply studied in animal models, there remain many open questions in human tumor immunology due to lack of tools to investigate human samples. We have developed genetic and genomics approaches to explain the large variance in anti-tumor immunity across people, and to discover how tumors evolve to resist productive immunity. We recently found that one of the best predictors of anti-tumor immunity is the load of neoantigens (mutated peptides presented on the surface of tumor cells on HLA molecules); we also identified somatic mutations in tumors that induce or resist anti-tumor immunity in patients (Rooney et al., Cell 2015). These studies are leading to novel therapeutic approaches and targets for immunotherapy. In particular, based on the finding that patients develop immunity against mutated neoantigens derived from their tumors (Hacohen et al., Cancer Immunology 2013; Rajasagi et al., Blood 2014), we have developed and are now testing a personalized tumor vaccine targeting multiple HLA-associated neoantigens in human tumors, together with Dr. Catherine Wu (DFCI).
Genes and networks underlying host-pathogen interactions
We have developed a set of integrative strategies to dissect networks of genes involved in sensing or controlling pathogens. We identified host pathways supporting or restricting influenza such as IFITM3 (Shapira et al., Cell 2009), transcription factors and signaling molecules mediating the innate immune responses to viruses and bacteria (Amit et al., Science 2009; Chevrier et al., Cell 2011), and components of innate DNA sensing (Lee et al., Nat Immun 2013). Most recently, we demonstrated that genome-wide CRISPR screens effectively discover genes involved in sensing pathogens (Parnas et al., Cell 2015), and are now using this system to discover genes involved in sensing diverse pathogens and controlling viral infections.
Genetic basis for inter-individual variations in immune responses
We have also developed genomic strategies to analyze human immune responses and explain immune phenotypes with germline genotypes. We discovered the genetic basis for inter-individual variation in the innate immune response to viruses and bacteria (Lee et al., Science 2014; Raj et al, Science 2014; Ye et al, Science 2014). For example, we found that common alleles of IRF7 tune the strength of an individual’s anti-viral response. Building on these studies, we have recently developed and are using systematic methods to analyze the role of genetic and non-genetic variations in human immunity and their impact on autoimmune diseases.
Innate immune drivers of autoimmunity
Deficiencies in nucleases that degrade DNA lead to accumulation of self DNA, activation of innate immune responses and development of autoimmune disorders, including systemic lupus erythematosus and Aicardi-Goutières syndrome in humans, and autoimmune arthritis, nephritis and myocarditis in mice. We have been interested in understanding how autoimmunity develops upon triggering of innate immunity by self DNA (rather than pathogen-derived DNA). In studying this question, we made the surprising observation that immunostimulatory DNA can arise from host damaged DNA that is exported from the nucleus to the lysosome (Lan et al, Cell Rep 2014). We hypothesize that this cellular process is a source of inflammation in autoimmunity, cancer, chemotherapy and aging. We also developed an integrated proteomic and genomic approach to uncover novel factors and small molecules targeting this pathway that may be useful to treat these diseases (Lee et al., Nat Imm 2013). To deepen our understanding of DNA and RNA pathways that drive autoimmunity, we are currently analyzing immune responses in lupus nephritis patients, with an emphasis on cellular and molecular analysis of kidney biopsies and blood samples from lupus patients.
A model for tumor-immune co-evolution by which: (a) intrinsic tumor factors -- such as mutated neoantigens, viruses or endogenous retroviruses -- induce local immune infiltrates (blue circles) that include cytolytic effector cells (CYT=cells expressing GZMA/PRF1; red circles) that kill tumors (daggers); (b) under pressure from cytolytic immune cells, tumor subclones are selected for resistance mutations (within the genes indicated) that autonomously evade killing or (c) non-autonomously suppress the immune infiltrate.
Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and Genetic Properties of Tumors Associated with Local Immune Cytolytic Activity. Cell. 2015 Jan 15;160(1-2):48-61.
Parnas O*, Jovanovic M*, Eisenhaure TM*, Herbst RH, Dixit A, Ye C, Przybylski D, Platt RJ, Tirosh I, Sanjana NE, Shalem S, Satija R, Raychowdhury R, Mertins P, Carr SA, Zhang F, Hacohen, N*, Regev A*. A Genome-wide CRISPR Screen in Primary Immune Cells to Dissect Regulatory Networks. Cell. 2015 Jul 30;162(3):675-86.
Lan YY, Londoño D, Bouley R, Rooney MS, Hacohen N. Dnase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy. Cell Reports. 2014 Oct 9;9(1):180-92.
Rajasagi M, Shukla SA, Fritsch EF, Keskin DB, DeLuca D, Carmona E, Zhang W, Sougnez C, Cibulskis K, Sidney J, Stevenson K, Ritz J, Neuberg D, Brusic V, Gabriel S, Lander ES, Getz G, Hacohen N, Wu CJ. Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. Blood. 2014 Jul 17;124(3):453-62.
Lee MN*, Ye C*, Villani AC, Raj T, Li W, Eisenhaure TM, Imboywa SH, Chipendo P, Ran FA, Slowikowski K, Ward LD, Raddassi K, McCabe C, Lee MH, Wood I, Kellis M, Raychaudhuri S, Zhang F, Stranger BE, Benoist CO, De Jager P, Regev A*, Hacohen N*. Common genetic variants modulate pathogen-sensing responses in human dendritic cells. Science. 2014, Mar 7;343(6175):1246980
Lee MN, Roy M, Ong SE, Mertins P, Villani AC, Li W, Dotiwala F, Sen J, Doench JG, Orzalli MH, Kramnik I, Knipe DM, Lieberman J, Carr SA, Hacohen N. Identification of regulators of the innate immune response to cytosolic DNA and retroviral infection by an integrative approach. Nature Immunology. 2013 Feb;14(2):179-85.
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