Faculty Bibliography

UNLABELLED:Myeloid malignancies are devastating hematologic cancers with limited therapeutic options. Inflammation is emerging as a novel driver of myeloid malignancy, with important implications for tumor composition, immune response, therapeutic options, and patient survival. Here, we discuss the role of inflammation in normal and malignant hematopoiesis, from clonal hematopoiesis to full-blown myeloid leukemia. We discuss how inflammation shapes clonal output from hematopoietic stem cells, how inflammation alters the immune microenvironment in the bone marrow, and novel therapies aimed at targeting inflammation in myeloid disease. SIGNIFICANCE:Inflammation is emerging as an important factor in myeloid malignancies. Understanding the role of inflammation in myeloid transformation, and the interplay between inflammation and other drivers of leukemogenesis, may yield novel avenues for therapy.

Highly coordinated changes in gene expression underlie T cell activation and exhaustion. However, the mechanisms by which such programs are regulated and how these may be targeted for therapeutic benefit remain poorly understood. Here, we comprehensively profile the genomic occupancy of mSWI/SNF chromatin remodeling complexes throughout acute and chronic T cell stimulation, finding that stepwise changes in localization over transcription factor binding sites direct site-specific chromatin accessibility and gene activation leading to distinct phenotypes. Notably, perturbation of mSWI/SNF complexes using genetic and clinically relevant chemical strategies enhances the persistence of T cells with attenuated exhaustion hallmarks and increased memory features in vitro and in vivo. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T expansion and results in improved anti-tumor control in vivo. These findings reveal the central role of mSWI/SNF complexes in the coordination of T cell activation and exhaustion and nominate small-molecule-based strategies for the improvement of current immunotherapy protocols.

Acute myeloid leukemia (AML) is a genetically heterogeneous, aggressive hematological malignancy induced by distinct oncogenic driver mutations. The effect of specific AML oncogenes on immune activation or suppression is unclear. Here, we examine immune responses in genetically distinct models of AML and demonstrate that specific AML oncogenes dictate immunogenicity, the quality of immune response and immune escape through immunoediting. Specifically, expression of Nras^G12D alone is sufficient to drive a potent anti-leukemia response through increased MHC Class II expression that can be overcome with increased expression of Myc. These data have important implications for the design and implementation of personalized immunotherapies for patients with AML.

Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor prognosis and limited treatment options. Here we provide a comprehensive census of the bone marrow immune microenvironment in adult and pediatric patients with AML. We characterize unique inflammation signatures in a subset of AML patients, associated with inferior outcomes. We identify atypical B cells, a dysfunctional B-cell subtype enriched in patients with high-inflammation AML, as well as an increase in CD8⁺GZMK⁺ and regulatory T cells, accompanied by a reduction in T-cell clonal expansion. We derive an inflammation-associated gene score (iScore) that associates with poor survival outcomes in patients with AML. Addition of the iScore refines current risk stratifications for patients with AML and may enable identification of patients in need of more aggressive treatment. This work provides a framework for classifying patients with AML based on their immune microenvironment and a rationale for consideration of the inflammatory state in clinical settings.

BACKGROUND:Adaptive CD19-targeted chimeric antigen receptor (CAR) T-cell transfer has become a promising treatment for leukemia. Although patient responses vary across different clinical trials, reliable methods to dissect and predict patient responses to novel therapies are currently lacking. Recently, the depiction of patient responses has been achieved using in silico computational models, with prediction application being limited. METHODS:) relapse. Real-time CAR T-cell and tumor burden data of 209 patients were collected from clinical studies and standardized with unified units in bone marrow. Parameter estimation was conducted using the stochastic approximation expectation maximization algorithm for nonlinear mixed-effect modeling. RESULTS:relapse. Furthermore, we predicted patient responses by combining the peak and accumulated values of CAR T-cells or by inputting early-stage CAR T-cell dynamics. A clinical trial simulation using virtual patient cohorts generated based on real clinical patient datasets was conducted to further validate the prediction. CONCLUSIONS:Our model dissected the mechanism behind distinct responses of leukemia to CAR T-cell therapy. This patient-based computational immuno-oncology model can predict late responses and may be informative in clinical treatment and management.

Clonal hematopoiesis (CH) is an aging-associated condition characterized by the clonal outgrowth of mutated pre-leukemic cells. Individuals with CH are at an increased risk of developing hematopoietic malignancies. Here, we describe a novel animal model carrying a recurrent TET2 missense mutation, frequently found in CH and leukemic patients. In a fashion similar to CH, animals show signs of disease late in life when they develop a wide range of myeloid neoplasms, including acute myeloid leukemia (AML). Using single cell transcriptomic profiling of the bone marrow, we show that disease progression in aged animals correlates with an enhanced inflammatory response and the emergence of an aberrant inflammatory monocytic cell population. The gene signature characteristic of this inflammatory population is associated to poor prognosis in AML patients. Our study illustrates an example of collaboration between a genetic lesion found in CH and inflammation, leading to transformation and the establishment of blood neoplasms.

Radium 223 (Ra223) is a bone-seeking, alpha-particle-emitting radionuclide approved for the treatment of patients with metastatic prostate cancer and is currently being tested in a variety of clinical trials for primary and metastatic cancers to bone. Clinical evaluation of Ra223 hematologic safety showed a significantly increased rate of neutropenia and thrombocytopenia in patients, hinting at myelosuppression as a side effect. In this study we investigate the consequences of Ra223 treatment on bone marrow biology. Ra223 accumulated in bones and induced zonal radiation damage confined at the bone interface, followed by replacement of the impaired areas with adipocyte infiltration, as monitored by three-dimensional multiphoton microscopy, ex vivo. Flow cytometry and single cell transcriptomic analyses on bone marrow hematopoietic populations revealed transient, non-specific Ra223-mediated cytotoxicity on resident populations, including stem, progenitor and mature leukocytes. This was paralleled by a significant decrease of white blood cells and platelets in peripheral blood, which was overcome within 40 days post-treatment. Ra223 exposure did not impair full hematopoietic reconstitution, suggesting that the bone marrow function is not permanently hampered. Our results provide a comprehensive explanation of Ra223 reversible effects on bone marrow cells and exclude long-term myelotoxicity, supporting its safety for patients.

The mutualistic relationship of gut-resident microbiota and the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a largely non-aggressive immune cell compartment^1,2. The consequences of disturbing this balance include proximal inflammatory conditions, such as Crohn's disease, and systemic illnesses. This equilibrium is achieved in part through the induction of both effector and suppressor arms of the adaptive immune system. Helicobacter species induce T regulatory (T_reg) and T follicular helper (T_FH) cells under homeostatic conditions, but induce inflammatory T helper 17 (T_H17) cells when induced T_reg (iT_reg) cells are compromised^3,4. How Helicobacter and other gut bacteria direct T cells to adopt distinct functions remains poorly understood. Here we investigated the cells and molecular components required for iT_reg cell differentiation. We found that antigen presentation by cells expressing RORγt, rather than by classical dendritic cells, was required and sufficient for induction of T_reg cells. These RORγt⁺ cells-probably type 3 innate lymphoid cells and/or Janus cells⁵-require the antigen-presentation machinery, the chemokine receptor CCR7 and the TGFβ activator α_v integrin. In the absence of any of these factors, there was expansion of pathogenic T_H17 cells instead of iT_reg cells, induced by CCR7-independent antigen-presenting cells. Thus, intestinal commensal microbes and their products target multiple antigen-presenting cells with pre-determined features suited to directing appropriate T cell differentiation programmes, rather than a common antigen-presenting cell that they endow with appropriate functions.