Immune cells in some human colorectal tumors congregate in clusters, scientists report in Cell.
Nir Hacohen, PhD
Director, MGH Center for Cancer Immunotherapy
Center for Cancer Research
Professor of Medicine, Harvard Medical School
Senior Member, Broad Institute
Center for Cancer Research
Antitumor Immunity and Its Evasion by Tumors
Recent findings show how T cells exert selection pressures on a tumor, influencing its genetic composition and future susceptibility to the immune system. Read More and listen to the podcast featuring Nir Hacohen.
Explore the Hacohen Lab
The Hacohen laboratory consists of immunologists, geneticists, biochemists, technologists, physicians and computational biologists working together to develop new and unbiased technologies and strategies to understand basic immune processes and immune-mediated diseases, with an emphasis on the innate immune system and personalized medicine. We address three key questions in immunology:
- How are immune responses against cancer initiated, maintained and evaded?
- What are the immune circuits that sense and control pathogens, such as viruses and bacteria?
- How does immunity against the body develop, in particular, in patients with autoimmune lupus
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 personal vaccine that is designed based on a computational analysis of their personal tumor genome.
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’ve identified somatic mutations in tumors that are associated with anti-tumor immunity in patients (Rooney et al., Cell 2015), discovered mutations in β2m in patients resistant to checkpoint therapy (Sade-Feldman et al., Nat Comm 2017) and found that TCF7+ T cells are associated with a response to anti-PD-1 immunotherapy in melanoma and are studying their properties now (Sade-Feldman et al., Cell 2019). We have also developed new methods to predict which tumor antigens are presented (Abelin et al., Immunity 2017, Sarkizova et al., Nat Biotech 2020), which are now being used to develop novel therapeutic approaches and targets for immunotherapy, such as personal tumor vaccines targeting multiple HLA-associated neoantigens in human tumors (together with Dr. Catherine Wu at DFCI, Ott et al., Nature 2017, Keskin Nature 2018).
Genes and networks underlying innate immunity
We’ve used genome-wide CRISPR libraries to discover mammalian genes mediating the sensing of pathogens (Parnas et al., Cell 2015), impacting HIV infection (Park et al, Nat Gen 2017) and affecting influenza infection (Li et al., Nat Comm 2020) and other sensing pathways (ongoing). We have also characterized innate myeloid cells (DCs and monocytes) in human blood as part of the human Immune Cell Atlas (Villani et al, Science 2017).
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 characterized 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, and that genetic control of splicing is prevalent and important for the immune response (Ye et al., Genome Res 2018). Building on these studies, we have recently developed and are now using systematic methods to analyze the role of genetic and non-genetic variations in human immunity.
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 (Lan et al., Aging Cell 2019). To deepen our understanding of pathways that drive autoimmunity, we have been analyzing immune responses in lupus nephritis patients, with an emphasis on cellular and molecular analysis of kidney biopsies and blood samples from lupus patients (Arazi et al., Nat Imm 2019) and more recently in comparison to animal models.
Reyes M, Filbin MR, Bhattacharyya RP, Billman K, Eisenhaure T, Hung DT, Levy BD, Baron RM, Blainey PC, Goldberg M, Hacohen N. An immune-cell signature of bacterial sepsis. Nature Medicine 2020. Mar;26(3):333-340.
Sarkizova S, Klaeger S, Le PM, Li LW, Oliveira G, Keshishian H, Hartigan CR, Zhang W, Braun DA, Ligon KL, Bachireddy P, Zervantonakis IK, Rosenbluth JM, Ouspenskaia T, Law T, Justesen S, Stevens J, Lane WJ, Eisenhaure T, Lan Zhang G, Clauser KR, Hacohen N, Carr SA, Wu CJ, Keskin DB. A large peptidome dataset improves HLA class I epitope prediction across most of the human population. Nat Biotechnol. 2020 Feb;38(2):199-209. doi: 10.1038/s41587-019-0322-9.
Arazi A, Rao DA, Berthier CC, Davidson A, Liu Y, Hoover PJ, Chicoine A, Eisenhaure TM, Jonsson AH, Li S, Lieb DJ, Zhang F, Slowikowski K, Browne EP, Noma A, Sutherby D, Steelman S, Smilek DE, Tosta P, Apruzzese W, Massarotti E, Dall’Era M, Park M, Kamen DL, Furie RA, Payan-Schober F, Pendergraft WF 3rd, McInnis EA, Buyon JP, Petri MA, Putterman C, Kalunian KC, Woodle ES, Lederer JA, Hildeman DA, Nusbaum C, Raychaudhuri S, Kretzler M, Anolik JH, Brenner MB, Wofsy D, Hacohen N, Diamond B; Accelerating Medicines Partnership in SLE network. The immune cell landscape in kidneys of lupus nephritis patients. Nature Immunology 2019. Jul;20(7):902-914.
Sade-Feldman M, Yizhak K, Bjorgaard SL, Ray JP, de Boer CG, Jenkins RW, Lieb DJ, Chen JH, Frederick DT, Barzily-Rokni M, Freeman SS, Reuben A, Hoover PJ, Villani A-C, Ivanova E, Portell A, Lizotte PH, Aref AR, Eliane JP, Hammond MR, Vitzthum H, Blackmon SM, Li B, Gopalakrishnan V, Reddy SM, Cooper ZA, Paweletz CP, Barbie DA, Stemmer- Rachamimov S, Flaherty KT, Wargo JA, Boland GM, Sullivan RJ, Getz G and Hacohen N. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell. 2018 Nov 1;175(4):998-1013.e20.
Ott P, Hu X, Keskin DB, Shukla SA, Sun J, Bozym DJ, Zhang W, Luoma A, Giobbie-Hurder A, Peter L, Chen C, Olive O, Carter TA, Li S, Lieb DJ, Eisenhaure T, Gjini E, Stevens J, Lane WJ, Javeri I, Nellaiappan K, Andreas Salazar12, Daley H, Seaman M, Buchbinder EI, Yoo CH, Harden M, Lennon N, Gabriel S, Rodig SJ, Barouch DH, Aster JC, Getz G, Wucherpfennig K, Neuberg D, Ritz J, Lander ES, Fritsch EF, Hacohen N & Wu CJ. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 2017, Jul 13;547(7662):217-221.
Villani A-C, Satija R, Reynolds G, Shekhar K, Fletcher J, Sarkizova S, Griesbeck M, Butler A, Zheng S,Lazo S, Jardine L, Dixon D, Stephenson E, McDonald D, Filby A, Li W, De Jager PL, Rozenblatt-Rosen O, Lane AA, Haniffa M, Regev A Hacohen N. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes and progenitors. Science 2017, Apr 21;356(6335).
HLA proteins present cancer-derived peptides to T cells and are among the most polymorphic genes in the human population. Shown here is a sampling of thousands of peptides (reduced to a 2D representation in which each dot is a peptide and each cluster represents biophysically related peptides) that we identified bound to 36 human HLA alleles which evolved under selection to present diverse peptides from a universe of pathogens.
Nir Hacohen, PhDPrincipal Investigator
- Matthew Bakalar, PhD
- Emily Blaum
- Rebecca Carlson*
- Sherry Chao*
- Jonathan Chen, MD, PhD
- Ang Cui*, MS
- Nora Donahue
- Thomas Eisenhaure
- Matteo Gentili, PhD
- Irena Gushterova
- Rebecca Holden, PhD
- Paul Hoover, MD, PhD
- Vjola Jorgji
- Alice Yuk Lan, PhD
- Bingxui Liu*
- Tom Lasalle
- David Lieb, MS
- Arnav Mehta, MD, PhD
- Karin Pelka, PhD
- Michael Peters
- Josh Pirl
- Raktima Raychowdhury, PhD
- Miguel Reyes*
- Moshe Sade-Feldman, PhD
- Sisi Sarkizova*, MS
- Alexis Schneider
- Marc Schwartz, MD, PhD
- Larry Schweitzer, PhD
- Molly Thomas
* PhD Candidates