RESEARCH projects

The anti-tumor immune response can be impacted positively and negatively by several major domains. Our lab is interested in factors from each of the domains and how they contribute to responsiveness or resistance to existing cancer immunotherapies.

Tumor oncogene-mediated immunotherapy resistance

Tumor molecular alterations can significantly impact the immune microenvironment, and consequently the responsiveness to immunotherapy. Our lab demonstrated that certain oncogenes, such as the fibroblast growth factor receptor-3 (FGFR3), are associated with the lack of an endogenous anti-tumor immune response at baseline. Clinical tumor samples from patients with FGFR3-altered tumors show a lack of immune infiltrating dendritic cells and T cells. These findings have been translated to clinical trials with combination-FGFR and anti-PD-1/L1 therapy, which have now demonstrated unprecedented rates of response >50% in patients with low expression of PD-L1. We are currently undergoing mechanistic investigation into how this tumor oncogene, and others, can directly or indirectly impact the anti-cancer immune response using preclinical models and multi-omic translational data on human cancer specimens.

Neoantigen quality impacts clinical outcome

Soon after anti-PD-1 immune checkpoint blockade became widely used, it was observed that the quantity of neoantigens in a cancer, also referred to as tumor mutational burden, was correlated with responsiveness to immune checkpoint therapy. Emerging data now indicates that characteristics of each neoepitope can impact the immune response. Some neoepitopes are more self-like and may induce regulatory T cell responses that are detrimental to the immune response. Machine learning technology can be used to select, based on nucleotide sequence, neoantigens most likely to induce a productive anti-tumor immune response. Through a collaboration with EpiVax, we employed the Ancer pipeline to identify high-quality neoepitopes from bladder cancer patients. Quantification predicted outcomes in bladder cancer with greater accuracy than unselected tumor mutational burden alone. Results from this work may guide the development of improved cancer vaccines strategies and biomarkers of immunotherapy responsiveness.

Germline genetics contribute to the immune response against cancer

Genetic predisposition to auto-immune disease has long been studied, however, our group has recently investigated the contribution of germline variants to the immune phenotypes in cancer. Rather than measure inherited risk of developing cancer, we are interested in understanding heritable factors that influence the immune response to cancer and how discoveries from these studies may also identify new therapeutic targets.

The commensal microbiome and its relationship to cancer immunotherapy

The human gut microbiome has been implicated in the responsiveness to cancer immunotherapies. Recently, the presence of a commensal urine microbiome has been identified in healthy volunteers and patients with nonmalignant conditions. We hypothesized that bladder cancer responsiveness to Bacillus Calmette-Guérin (BCG) immunotherapy may be impacted by the commensal urine microbiome. We are conducting an analysis from a prospective study to determine potential biomarkers of BCG responsiveness and therapeutic strategies to improve outcomes. We also aim to reverse-translate these findings into preclinical models.