Research in my laboratory is focused on the discovery and characterization of cancer biomarkers and novel druggable targets. In my lab we use integrative genomic approaches to identify genetic and cellular properties of tumors that explain systems-level variation in cancer aggressiveness and treatment response. We employ next-generation sequencing technologies such as whole-exome sequencing, bulk RNA-Seq and single-cell RNA-Seq to study how the molecular and cellular composition of tumors impacts tumor form and phenotype. In breast cancers and other solid tumors, we investigate the dynamics of tumor-immune interactions on a population scale. Our work shows that biomarkers predictive of immune-mediated patient outcomes reflect differences in tumor immunological configurations, as well as states of molecular polarization that favor immunosuppressive or immunostimulatory phenotypes. Using multivariable statistics to guide the discovery process, we have identified novel molecular interactions between tumors and their immunological environments that are the focus of ongoing mechanistic studies involving immunocompetent mouse tumor models and immune functional characterization assays.

Prognostic and predictive breast cancer immune subclasses

Through analysis of the tumor transcriptome, we have gained detailed insights into the pathobiology of cancer and its clinical manifestations. Immunological gene networks that reflect the abundance of distinct tumor-infiltrating leukocyte populations can be quantified in breast tumors and are predictive of multiple clinical endpoints. Key among them are signatures of cytolytic CD8+ T cells and antibody-producing plasma B cells that show strong and independent statistical associations with reduced cancer recurrence, positive neoadjuvant drug response and long-term overall survival of patients. We find that immune-mediated breast cancer survival is significantly linked to tumors with high proliferative capacity or high mutational burden, and is measurable in all breast cancer subtypes. Conversely, tumors absent of these signatures are defined by poor clinical outcomes, high intratumoral TGF-beta expression, and chromosomal amplification of immune-modulatory genes that may potentiate immune evasion. We are currently investigating the implications of these findings for emerging immunotherapeutic treatments for breast cancer. 

Mechanisms of immunosuppression

Using tumor gene expression and mutational profiles, we have developed genetic triangulation algorithms to pinpoint cancer oncogenes and pathways of cancer progression. In this framework, we are studying hypotheses related to: 1) druggable myeloid-derived signaling cascades that orchestrate the recruitment, expansion and survival of immunosuppressive myeloid cells at the tumor site that inhibit anti-tumor immunity and promote breast cancer malignant progression through paracrine signaling, and 2) the discovery of tumor-agnostic transcriptional programs exploited by tumors to evade immune destruction by inhibiting the trafficking and subsequent activation of effector T cells. 

Other current and collaborative research interests include

  • Blood-based biomarkers of immunotherapy response
  • Use of patient-derived tumor organoids to track treatment-induced changes in tumor clonal architecture
  • Characterization of immunomodulatory tumor microenvironments by scRNA-Seq
  • Development of molecular signatures to guide clinical decision making for appendiceal cancer
  • Blockade of TREM-1 signaling in myeloid-derived suppressor cells to enhance efficacy of immune checkpoint inhibitors