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Understanding Tumor Immunobiology

Our group is interested in how measurements of the tumor immune microenvironment can be used to predict clinical outcomes and inform effective combination immunotherapy strategies. To investigate this, we combine immunogenomics with classical cellular and molecular immunology techniques. Our work has highlighted the importance of antigen-specific B cell responses in breast cancer, bladder cancer, and other solid tumors (see publications).

We have been a leading lab in identifying molecular subtype-specific differential immune responses in breast and bladder cancer (see publications), work that is becoming increasingly important as molecular subtype has been associated with clinical response to immune checkpoint inhibition in these tumors. To further map immune response heterogeneity to tumor genomic heterogeneity, we have analyzed novel mouse models of bladder cancer developed by William Kim to confirm their molecular subtypes and differential immune responses mirror those of human bladder cancer. We have discovered conditions for which these tumors produce mixed responses to immune checkpoint inhibition (i.e. some animals have tumor regression with therapy while others have tumors that progress). These immunocompetent models uniquely allow us to study differential immune responses as well as discover mechanisms of response versus resistance to immunotherapy in bladder cancer.


Developing Novel Immunogenomics Tools

We are heavily invested in creating tools to answer otherwise inaccessible questions in tumor immunology. We have developed statistical techniques for analysis of high dimensional T cell receptor (TCR) and B cell receptor (BCR) repertoire data (publication), approaches for inference of TCR and BCR repertoire features from short-read RNA sequencing data (publication), a method for mapping single-cell TCR data to proteomics parameters measurable by flow cytometry (publication), and pioneering techniques for immune gene signature analysis of human tumors (see publications). To support ongoing and future work, we have also developed pipelines for prediction of neoantigens and minor histocompatibility antigens using next-generation sequencing data. Beyond genomics, we have worked with the Parrott Laboratory to develop a positron-emission tomography in vivo imaging method to visualize and quantify T cells in the tumor immune microenvironment.

 


Understanding Response and Resistance to Combination Immunotherapy

We work closely with clinical investigators to develop and test novel combination immunotherapy strategies in the bedside-to-bench-to-bedside model: identifying important immunotherapy applications in the clinic, using pre-clinical models to evaluate mechanisms of treatment response and test new strategies to improve efficacy, and designing clinical trials informed by the pre-clinical data. We currently are working on correlative analyses of samples from multiple clinical protocols we helped to develop, including studying PD-1 inhibition following regulatory T cell depletion in metastatic triple negative breast cancer (LCCC1525, with adjuvant gemcitabine/cisplatin chemotherapy in bladder cancer (LCCC1520), and with high-dose cytarabine in relapsed acute myeloid leukemia (LCCC1522). In collaboration with the LCCC Mouse Phase I Unit, we are able to mirror the human breast and bladder cancer trials using subtype specific, immunocompetent pre-clinical models, which allow us to investigate mechanisms of response versus resistance as well as test new therapeutic combinations to inform future clinical trials.


Targeting Neoantigens and Minor Histocompatibility Antigens for Personalized Immunotherapy

We are studying combination immunotherapy strategies that include generation of T cells targeting tumor-specific neoantigens or minor histocompatibility antigens. Neoantigens are altered peptides derived from mutant proteins that are presented by major histocompatibility complex (MHC) molecules and drive robust anti-tumor T cell responses. Neoantigen peptides are especially attractive tumor vaccine or cell therapy targets given their tumor specificity and lack of T cell tolerance induction. In the context of allogeneic stem cell transplantation (alloSCT), minor histocompatibility antigens (mHA) are variant peptides present in recipient but not donor proteins that are derived from genetic variants between the donor and recipient and are presented by recipient MHC to stimulate mHA-specific T cells. These T cells can engage and kill recipient tumor cells that express cognate mHA, thereby promoting remission and cure, a process known as the graft-versus-tumor effect (GvT). Unfortunately, not all mHA-reactive T cells are beneficial. A major complication of alloSCT is graft-versus-host disease (GvHD), in which T cells target mHA expressed by recipient epithelial cells causing inflammatory tissue injury that can be fatal. Our group has developed bioinformatics pipelines to predict neoantigens and mHA, and we are investigating uses of these to develop biomarkers of response to immune checkpoint inhibition and test novel tumor-specific immunotherapy strategies in vivo.


The Cancer Genome Atlas Immune Response Working Group

We are active contributors to The Cancer Genome Atlas (TCGA) Immune Response Working Group, on which Dr. Vincent serves as co-chair along with V├ęsteinn Thorsson and Ilya Shmulevich of the Institute for Systems Biology in Seattle, WA.