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, found T cell subtypes that are associated with a response to anti- PD-1 immunotherapy in melanoma and are studying their properties now (Sade-Feldman et al., Cell 2018), and discovered spatially-organized immune cell hubs in colon cancer (Pelka, Hofree, Chen et al, Cell 2021; Chen et al, bioRxiv 2023). 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, especially 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).

Genetic and non-genetic basis for inter-individual variations in immune responses (including sepsis)

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 developed and are now using systematic methods to analyze the role of genetic variants (Ray et al., Nat Comm 2021; Mouri, Nat Genetics, 2022). We also study non-genetic variations in human immunity, and found a myeloid cell type and state (‘MS1’ that corresponds to MDSCs) strongly associated with severe infections (bacterial and viral, including COVID-19) and sepsis (Reyes et al, Nat Med 2020, Science Tr Med 2021), leading us to new hypotheses underlying these dangerous clinical trajectories, which we are now studying in mouse models

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 further find drivers of 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 in a small (Arazi et al., Nat Imm 2019) and large patient cohort (>150 patients) and more recently in comparison to animal lupus models.

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). We have also defined regulators of viral RNA-sensing (Carlson et al., PNAS 2023) and DNA-sensing pathways using FACS- and imaging-based screens. Recently, we discovered that the STING protein, a protein required for sensing cyclic di-nucleotides, is a proton channel that can trigger LC3B lipidation, inflammasome activation and cell death (Liu, Carlson et al., Science 2023).”