Our Research

In recent years, new tools have emerged that permit incredible and detailed study of biological systems. We seek to apply these new technologies to the study of T cells and to the study of immunology more broadly.

A key area of research is the application of next-generation sequencing (NGS) to immunological questions. Our work routinely uses mRNA-sequencing, single-cell RNA-sequencing, T cell receptor-sequencing, spatial transcriptomics, and similar NGS methods to assay T cell phenotype and function. Importantly, we seek to tailor these methods and develop new applications for the study of immunology. Recently, we published work developing a method to obtain T cell receptor sequences – a molecule barcode to identify similar T cells – from intact tumor tissue using spatial transcriptomics. In a related paper, this method allowed us to demonstrate that exhausted T cells locate to specific regions within the tumor microenvironment, where they receive distinct signals to control their function. This work may identify new signaling pathways that can be targeted in cancer immunotherapy.

We also work to develop high-quality, multiple-parameter flow cytometry panels to obtain large amounts of phenotypic information from immune cells. This is critical to obtain detailed information from samples where cell number is limited. For phenotypic analysis, we combine flow cytometry with NGS to create detailed pictures of immune function. We recently published work combining deep mutational scanning, flow cytometry, and NGS to generate a high-throughput screen to identify all possible escape mutations for antibodies against the SARS-CoV-2 nucleoprotein. This study is critical in showing the continued function of rapid antigen tests against new variants of SARS-CoV-2.

“Exhaustion” is the process by which T cells become dysfunctional and fail to control tumors and infections. By understanding the biology of T cell exhaustion, we can identify new targets and strategies to improve T cell function.
Our research has shown that T cell exhaustion is a gradual process. Immediately after viral infection or generation of a tumor, T cells are highly functional and capable of killing target cells. However, if the viral infection or tumor is not cleared, T cells become progressively more dysfunctional. Eventually, these cells are incapable of functions - such as division, cytokine production, and target killing – that are critical to anti-viral and anti-tumor immunity. A key focus of our current research is understanding the mechanism that drives T cells to dysfunction.

To answer this question, we create genetically-modified T cells to study the roles of specific genes in inducing or preventing T cell dysfunction in models of viral infection and cancer. We use both traditional genetic techniques and CRISPR/Cas9 to directly modify primary T cells and study their function. We then measure the ability of these T cells to directly combat tumor growth and virus replication in cancer and infection models. We use high-parameter flow cytometry, mRNA-sequencing, T cell receptor-sequencing, and single-cell RNA-sequencing to characterize the phenotype of these cells and perform functional assays such as cytokine secretion measurement to identify genes causing disruption or enhancing of direct T cell functionality.

In addition to our model organism work, we have a deep interest in characterizing the immune landscape of human tumors, with a specific focus on T cells. Our recent work performed a comprehensive characterization of cytotoxic T cells in patients with brain metastases. Analysis of patient tumors allows us to identify clinically-relevant signaling pathways to investigate in our preclinical research programs. Overall, the goal of this research program is to identify new targets and therapeutic strategies for the immunotherapy of viral infection, autoimmunity, and cancer.

Immunotherapies – modification of the immune system to treat diseases – have revolutionized the treatment of cancer. Unfortunately, not all patients respond to current immunotherapies. We seek to identify new strategies and drugs to improve T cell responses in patients cancer and infectious disease.

Our work on T cell exhaustion focuses on the signals that T cells receive as they attempt to kill infected and tumor cells. Often, the targeted cells themselves attempt to suppress T cell function by sending inhibitory signals to modulate the attacking T cell. Other cells present near T cells may present inhibitory or stimulatory signals; these stimulatory signals further activate T cells in an attempt to improve the immune response against a tumor or virus. T cells can be further affected by cytokines or hormones that can travel long distances to regulate their function.

Thus, T cell function is often in a delicate balance between stimulatory and inhibitory signals received from its target cells and other cells within the tissue. Our goal is to develop new strategies and therapies to tip the balance of T cell function toward the killing of cancer and virus-infected cells. Such treatments are termed “immunotherapies” and have revolutionized treatment of many tumor types. Unfortunately, most patients do not respond to immunotherapies and more options are needed.

We are currently working to dissect novel inhibitory T cell signaling pathways in order to design new therapies to improve T cell responses. We target these pathways by genetic modification of T cells, which will be applicable to improving cell therapies such as CAR T cells. We also work to test the effects of therapeutic antibodies against co-inhibitory proteins in preclinical models. Finally, we are also interested in using our immunology and bioinformatics expertise to identify tumor-specific T cells within patient tumors to find T cell receptors that can be used in adoptive cell therapy.