Timothy N. Bullock
Primary AppointmentAssociate Professor, Pathology
- PhD, Thomas Jefferson University
Pathways to enhance T cell function in tumors.
DC are extremely potent antigen presenting cells (APC) that express MHC class I and class II molecules and an array of costimulatory molecules that are required for the activation of naïve T cells. Recent studies have demonstrated that many patients make immune responses against their tumors, though they usually ultimately fail to control tumor outgrowth. While multiple reasons exist for the loss of immune control of tumors, one that we are focusing on is the lack of costimulation in the tumor microenvironment leads to dysfunctional T cell responses. Thus, we hope to understand how DC regulation of T cell responses can be parlayed into more effective immunostimulatory approaches.
Extensive investigations have identified many of the proteins that are the targets of anti-tumor immune responses, and further defined the MHC class I and MHC class II-restricted peptides derived from tumor antigens that are presented to cytotoxic CD8+- and helper CD4+ T cells respectively. As we now understand that many tumors can auto-vaccinate (i.e. contain many mutations that can be sensed by T cells), approaches that increase DC function, or directly stimulate T cells, can enhance anti-tumor T cell responses.
As a consequence of our interest in how CD4+ T cells influence CD8+ T cell responses to tumor (Hwang 2007), our lab has also shown that one of the essential consequences of activating DC is the upregulation of the TNF-superfamily member, CD70 (Bullock, 2005). We have found that the expression of CD70 on DC is not only a biomarker of potently activated DC, but the costimulation rendered by CD70, via its receptor CD27 (which is expressed on most naïve T and B cells, and a subset of NK cells) strongly influences both CD8+ T cell and CD4+ T cell responses to vaccines. We have worked on optimizing the induction of CD70 expression by activated CD4+ T cells (Van Deusen, 2009); understanding how CD70-CD27 costimulation regulates the ability of CD8+ T cells to form effector and memory CD8+ T cells (Dong, 2012); and have led studies revealing how CD27 stimulation can be used to augment anti-tumor immune responses (Roberts, 2010). Current projects in the lab involve:
1. Defining the mechanism by which CD27 stimulation promotes the generation of CD8+ T cell responses to peptide/protein immunization.
These studies encompass the basic biology of how CD27 stimulation promotes the expression of the IL-7R and concomitantly protects CD8+ T cells from IL-12-induced AICD. Practical applications include the use of CD27 stimulation for next-generation vaccines for cancer (in clinical trials at UVA) and for infectious disease platforms. We are currently also understanding the transcriptional networks that are regulated by CD70-CD27 during T cell activation and differentiation.
2. Defining how to utilize CD70/CD27-mediated costimulation to enhance immunological control of tumor.
These studies are focused on optimizing the induction of CD70 expression in the tumor microenvironment (TME) and understanding the alterations in immune cell (CD8+ T cell; CD4+ T cell and NK cell) function in the tumor after CD27 stimulation. These studies have taken us down two complimentary pathways. First, we have identified transcriptional alterations within tumor infiltrating lymphocytes (TIL), primarily regulated by the transcriptional repressor, BLIMP-1. We are studying how BLIMP-1 is induced within TIL, and what functions are regulated by BLIMP-1. Second, CD27 stimulation augments the functional status of T cells in tumors; recent data suggests that this is achieved by promoting the metabolic activity of TIL. Therefore, we are now embarked on defining how the metabolic state of TIL influences their function, and what metabolic states are needed to optimize TIL activity within tumors.
As our lab is committed to multi-disciplinary, team-based research, we interact with many partner labs at UVA. Examples of this include:
1.Using phage-display libraries to define proteomic alterations that are exhibited by tumor-infiltrated lymphocytes with the intent of identifying novel, targetable inhibitory molecules (Kelly lab, Biomedical Engineering)
2.The use of focused-ultrasound (FUS) to promote immune activity within the TME (Price lab, Biomedical Engineering);
3. The co-development of targeted therapies with immunotherapies (Gioeli/Weber labs, Microbiology).
Consequentially, we are a highly translation-focused lab, participating in Phase I clinical trials for the fully human agonistic antibody for CD27 (Celldex Therapeutics); an exploratory study using stereotactic-radiation and either immune costimulation (CD27) or checkpoint blockade (anti-CLTA-4 or PD-1) for prostate cancer (Larner/Showalter, Radiation Oncology); and the use of either CD27 or CD40 agonistic antibodies to augment peptide vaccines for melanoma (Slingluff lab, Surgical Oncology). By understanding the extent of activation and differentiation of the responding T cells, both in blood and in the tumor, we hope to determine whether any deficiencies exist in the patient's T cell response, and whether additional interventions may overcome such deficiencies.