With a revolution in cancer immunotherapy under way, many fundamental questions remain about how tumors and immune cells interact, why some patients respond or don’t respond to immunotherapy, and what are the next targets for therapy. Our projects address these questions and are generating many new discoveries and directions in this rapidly growing area.
T cell dysfunction/exhaustion in tumors
T cell dysfunction or “exhaustion” is a phenotype in which so-called “coinhibitory” or “checkpoint” receptors, such as PD-1 and CTLA-4, on the surface of CD8+ T cells are expressed over long periods of time and accumulate on the cell surface. Blocking these receptors has proven to be a successful immunotherapeutic strategy against cancer. Although these receptors have a clear role in T cell dysfunction, the mechanism by which this occurs is unknown. One coinhibitory receptor, Tim-3, has recently been shown to mark the most severely “exhausted” or dysfunctional T cells that arise in chronic viral infections, such as HIV and HCV, as well as in cancer. Agents that interfere with Tim-3 signaling are now in development for clinical trials in cancer. Currently, we are studying the pathways that drive expression of this receptor and the biochemical pathways by which it mediates its effects in T cells.
Team members: Regev, Anderson, Kuchroo, Hacohen
Mechanisms of immune evasion and exhaustion
Blockade of T cell inhibition using immune checkpoint inhibitors has shown marked effectiveness in a variety of cancers, but many patients relapse or fail to respond. Relapse after an initial response may represent the escape of tumor cells from the equilibrium of immunosurveillance, and may be mediated by tumor-derived inhibitory factors. In order to identify additional molecules capable of modulating the immune response, we are using methods of human genetics, CRISPR technology, and in vivo loss of function screens in mouse tumor models.
Team members: Haining, Hacohen
Costimulation of immune cells
Costimulatory molecules are critical in T cell activation. Learning how to manipulate costimulatory pathways may provide new therapeutic approaches for augmenting immunity to microbes and tumor antigens, as well as for inhibiting immune responses to prevent graft rejection and treat autoimmune diseases. Several projects in mice and humans are analyzing the roles of multiple costimulators and coinhibitors in the T cell response.
Team members: Sharpe, Kuchroo, Anderson
Single-cell profiling of tumor immune infiltrates
We are using spatially-resolved single-cell transcriptomics to define the heterogeneous state of immune cells in the tumor microenvironment and identify the cellular circuits that enable immune evasion by tumor cells. We believe that our work will yield a powerful pipeline applicable to all cancers, including those that have thus far proven to be largely resistant to immunotherapy.
Team members: Garraway, Regev, Hacohen, Shalek, Haining
Human cancer immunology and immunotherapy
While cancer immunology has been deeply studied in animal models, there remain many open questions in human tumor immunology due to a lack of tools for investigating human samples. We have developed genetic and genomic approaches to probe 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.
These studies are leading to novel therapeutic approaches and targets for immunotherapy. For example, based on the finding that patients develop immunity against mutated neoantigens derived from their tumors, we have developed and are now testing personalized tumor vaccines targeting multiple HLA-associated neoantigens in human cancers.
Team members: Hacohen, Wu
As a Broad scientific and medical community, and in collaboration with leading hospitals in the Boston area, we are studying brain tumors, both in children and adults, with a particular focus on low-grade gliomas (grade II), anaplastic gliomas (grade III), and glioblastoma (GBM, grade IV). Significant efforts include comprehensive genomic characterization of human gliomas of all grades leading to new insights into tumor classification and genetic drivers of disease.
Our community has pioneered single-cell genomics to characterize patient tumors at the single-cell level, shedding important light on tumor heterogeneity. We are investigating changes that affect the epigenome of gliomas, dissecting aberrant epigenetic states and epigenetic mechanisms of drug resistance, as well as altered developmental and metabolic pathways. To explore novel therapeutic options, we are performing high-throughput chemical screenings and have now studied the resistance patterns of GBM to more than 400 unique compounds.
Additionally, as part of a major endeavor around cancer vaccines, we are now enabling clinical trials in GBM to target personalized neoantigens based on sequencing of patient tumors. Overall, the Broad community is placing significant efforts and making contributions to the understanding and management of these dismal pathologies.