Skip to main content
Timothy N. Bullock, PhD

Timothy N. Bullock, PhD

Professor of Pathology, Pathology

Primary Location
PO Box 801386
MR-6 G527
Charlottesville, VA 22908
Primary Phone Number
434.982.1932
Fax Number
434.924.9824
Email
[email protected]

Bio & Overview

The focus of our work is on the use of costimulatory pathways, particularly the CD70-CD27 TNF-superfamily members, to promote immunotherapeutic T cell responses against melanoma and other malignancies, and as a platform for vaccine delivery. 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.

Academic Information

Department
Pathology
Academic Title
Associate Professor

Primary Education

  • PhD, undefinedThomas Jefferson University, 1996

Other Appointments

  • Associate Professor, Microbiology, Immunology, and Cancer Biology
  • Associate Professor, MII
  • Associate Professor, MOMD

Other Affiliations

  • Member, Immunology/Immunotherapy Program
  • MSTP
  • Associate Professor, BIMS

Research Interests

Pathways to enhance T cell function in tumors.

Research Disciplines

  • Cancer Biology
  • Experimental Pathology
  • Immunology
  • Infectious Diseases/Biodefense
  • Translational Science

Research Opportunities

  • Cancer Biology
  • Cancer Immunology and Immunotherapy
  • Cellular and Molecular Metabolism
  • Experimental Pathology
  • Immunology

PhD Programs

  • Experimental Pathology
  • Microbiology

Selected Publications

2024

Wessel, R. E., Ageeb, N., Obeid, J. M., Mauldin, I., Goundry, K. A., Hanson, G. F., . . . Brown, M. G. (2024). Spatial colocalization and combined survival benefit of natural killer and CD8 T cells despite profound MHC class I loss in non-small cell lung cancer.. bioRxiv. doi:10.1101/2024.02.20.581048

Shi, X., Facemire, L., Singh, S., Kumar, S., Cornelison, R., Liang, C., . . . Li, H. (2024). UBA1-CDK16 : A Sex-Specific Chimeric RNA and Its Role in Immune Sexual Dimorphism.. bioRxiv. doi:10.1101/2024.02.13.580120

Thim, E. A., Kitelinger, L. E., Rivera-Escalera, F., Mathew, A. S., Elliott, M. R., Bullock, T. N. J., & Price, R. J. (2024). Focused ultrasound ablation of melanoma with boiling histotripsy yields abscopal tumor control and antigen-dependent dendritic cell activation.. bioRxiv. doi:10.1101/2023.09.02.552844

2023

Stevens, M. G., Mason, F. M., & Bullock, T. N. J. (2024). The mitochondrial fission protein DRP1 influences memory CD8+T cell formation and function. JOURNAL OF LEUKOCYTE BIOLOGY, 115(4), 679-694. doi:10.1093/jleuko/qiad155

Padilla, F., Foley, J., Timbie, K., Bullock, T. N. J., & Sheybani, N. D. (2023). Guidelines for immunological analyses following focused ultrasound treatment. JOURNAL FOR IMMUNOTHERAPY OF CANCER, 11(11). doi:10.1136/jitc-2023-007455

Conarroe, C. A., & Bullock, T. N. J. (2023). Ready for Prime Time? Dendritic Cells in High-Grade Gliomas. CANCERS, 15(11). doi:10.3390/cancers15112902

Gamache, A., Conarroe, C., Adair, S., Bauer, T., Padilla, F., & Bullock, T. N. J. (2023). Interrogating the CD27:CD70 axis in αCD40-dependent control of pancreatic adenocarcinoma. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, 11. doi:10.3389/fcell.2023.1173686

2022

Price, R. J., Bullock, T. N. J., & Sheybani, N. D. (2022). Letter to the editor regarding "Translation of focused ultrasound for blood-brain barrier opening in glioma". JOURNAL OF CONTROLLED RELEASE, 349, 16-17. doi:10.1016/j.jconrel.2022.06.041

Bullock, T. N. J. (2022). CD40 stimulation as a molecular adjuvant for cancer vaccines and other immunotherapies (vol 19, pg 14, 2021). CELLULAR & MOLECULAR IMMUNOLOGY, 19(7), 866. doi:10.1038/s41423-022-00865-2

2021

Sheybani, N. D., Witter, A. R., Garrison, W. J., Miller, G. W., Price, R. J., & Bullock, T. N. J. (2022). Profiling of the immune landscape in murine glioblastoma following blood brain/tumor barrier disruption with MR image-guided focused ultrasound. JOURNAL OF NEURO-ONCOLOGY, 156(1), 109-122. doi:10.1007/s11060-021-03887-4

Mills, A. M., Bullock, T. N., & Ring, K. L. (2022). Targeting immune checkpoints in gynecologic cancer: updates & perspectives for pathologists. MODERN PATHOLOGY, 35(2), 142-151. doi:10.1038/s41379-021-00882-y

Noffsinger, B., Witter, A., Sheybani, N., Xiao, A., Manigat, L., Zhong, Q., . . . Purow, B. (2021). Technical choices significantly alter the adaptive immune response against immunocompetent murine gliomas in a model-dependent manner. JOURNAL OF NEURO-ONCOLOGY, 154(2), 145-157. doi:10.1007/s11060-021-03822-7

Bullock, T. N. J. (2022). CD40 stimulation as a molecular adjuvant for cancer vaccines and other immunotherapies. CELLULAR & MOLECULAR IMMUNOLOGY, 19(1), 14-22. doi:10.1038/s41423-021-00734-4

Stevens, A. D., & Bullock, T. N. J. (2021). Therapeutic vaccination targeting CD40 and TLR3 controls melanoma growth through existing intratumoral CD8 T cells without new T cell infiltration. CANCER IMMUNOLOGY IMMUNOTHERAPY, 70(8), 2139-2150. doi:10.1007/s00262-020-02841-z

Dusenbery, A. C., Maniaci, J. L., Hillerson, N. D., Dill, E. A., Bullock, T. N., & Mills, A. M. (2021). MHC Class I Loss in Triple-negative Breast Cancer A Potential Barrier to PD-1/PD-L1 Checkpoint Inhibitors. AMERICAN JOURNAL OF SURGICAL PATHOLOGY, 45(5), 701-707. doi:10.1097/PAS.0000000000001653

2020

Bullock, T. N. J. (2021). Fundamentals of Cancer Immunology and Their Application to Cancer Vaccines. CTS-CLINICAL AND TRANSLATIONAL SCIENCE, 14(1), 120-131. doi:10.1111/cts.12856

Seki, S. M., Posyniak, K., McCloud, R., Rosen, D. A., Fernandez-Castaneda, A., Beiter, R. M., . . . Gaultier, A. (2020). Modulation of PKM activity affects the differentiation of TH17 cells. SCIENCE SIGNALING, 13(655). doi:10.1126/scisignal.aay9217

Friedman, L. A., Bullock, T. N., Sloan, E. A., Ring, K. L., & Mills, A. M. (2021). MHC class I loss in endometrial carcinoma: a potential resistance mechanism to immune checkpoint inhibition. MODERN PATHOLOGY, 34(3), 627-636. doi:10.1038/s41379-020-00682-w

Duska, L. R., Scalici, J. M., Temkin, S. M., Schwarz, J. K., Crane, E. K., Moxley, K. M., . . . Showalter, T. N. (2020). Results of an early safety analysis of a study of the combination of pembrolizumab and pelvic chemoradiation in locally advanced cervical cancer. CANCER, 126(22), 4948-4956. doi:10.1002/cncr.33136

Sheybani, N. D., Witter, A. R., Thim, E. A., Yagita, H., Bullock, T. N. J., & Price, R. J. (2020). Combination of thermally ablative focused ultrasound with gemcitabine controls breast cancer via adaptive immunity. JOURNAL FOR IMMUNOTHERAPY OF CANCER, 8(2). doi:10.1136/jitc-2020-001008

Curley, C. T., Stevens, A. D., Mathew, A. S., Stasiak, K., Garrison, W. J., Miller, G. W., . . . Price, R. J. (2020). Immunomodulation of intracranial melanoma in response to blood-tumor barrier opening with focused ultrasound. THERANOSTICS, 10(19), 8821-8833. doi:10.7150/thno.47983

2019

Wages, N. A., Slingluff, C. L. J., Bullock, T. N., & Petroni, G. R. (2020). Tailoring early-phase clinical trial design to address multiple research objectives. CANCER IMMUNOLOGY IMMUNOTHERAPY, 69(1), 95-102. doi:10.1007/s00262-019-02442-5

Dong, H., Buckner, A., Prince, J., & Bullock, T. (2019). Frontline Science: Late CD27 stimulation promotes IL-7Rα transcriptional re-expression and memory T cell qualities in effector CD8+ T cells. JOURNAL OF LEUKOCYTE BIOLOGY, 106(5), 1007-1019. doi:10.1002/JLB.1HI0219-064R

Shin, M., Buckner, A., Prince, J., Bullock, T. N. J., & Hsu, K. -L. (2019). Diacylglycerol Lipase-β Is Required for TNF-α Response but Not CD8+ T Cell Priming Capacity of Dendritic Cells. CELL CHEMICAL BIOLOGY, 26(7), 1036-+. doi:10.1016/j.chembiol.2019.04.002

Gemta, L. F., Siska, P. J., Nelson, M. E., Gao, X., Liu, X., Locasale, J. W., . . . Bullock, T. N. J. (2019). Impaired enolase 1 glycolytic activity restrains effector functions of tumor-infiltrating CD8+ T cells. SCIENCE IMMUNOLOGY, 4(31). doi:10.1126/sciimmunol.aap9520

2018

Shi, L., Li, K., Guo, Y., Banerjee, A., Wang, Q., Lorenz, U. M., . . . Krupnick, A. S. (2018). Modulation of NKG2D, NKp46, and Ly49C/I facilitates natural killer cell-mediated control of lung cancer. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 115(46), 11808-11813. doi:10.1073/pnas.1804931115

Volaric, A., Gentzler, R., Hall, R., Mehaffey, J. H., Stelow, E. B., Bullock, T. N., . . . Mills, A. M. (2018). Indoleamine-2,3-Dioxygenase in Non-Small Cell Lung Cancer A Targetable Mechanism of Immune Resistance Frequently Coexpressed With PD-L1. AMERICAN JOURNAL OF SURGICAL PATHOLOGY, 42(9), 1216-1223. doi:10.1097/PAS.0000000000001099

Borne, A. L., Huang, T., McCloud, R. L., Pachaiyappan, B., Bullock, T. N. J., & Hsu, K. -L. (2019). Deciphering T Cell Immunometabolism with Activity-Based Protein Profiling. ACTIVITY-BASED PROTEIN PROFILING, 420, 175-210. doi:10.1007/82_2018_124

Dill, E. A., Dillon, P. M., Bullock, T. N., & Mills, A. M. (2018). IDO expression in breast cancer: an assessment of 281 primary and metastatic cases with comparison to PD-L1. MODERN PATHOLOGY, 31(10), 1513-1522. doi:10.1038/s41379-018-0061-3

Mills, A. M., Dill, E. A., Moskaluk, C. A., Dziegielewski, J., Bullock, T. N., & Dillon, P. M. (2018). The Relationship Between Mismatch Repair Deficiency and PD-L1 Expression in Breast Carcinoma. AMERICAN JOURNAL OF SURGICAL PATHOLOGY, 42(2), 183-191. doi:10.1097/PAS.0000000000000949

Knapp, K. A., Pires, E. S., Adair, S. J., Mandal, A., Mills, A. M., Olson, W. C., . . . Herr, J. C. (2018). Evaluation of SAS1B as a target for antibody-drug conjugate therapy in the treatment of pancreatic cancer.. Oncotarget, 9(10), 8972-8984. doi:10.18632/oncotarget.23944

Melssen, M. M., Olson, W., Wages, N. A., Capaldo, B. J., Mauldin, I. S., Mahmutovic, A., . . . Slingluff, C. L. J. (2018). Formation and phenotypic characterization of CD49a, CD49b and CD103 expressing CD8 T cell populations in human metastatic melanoma. ONCOIMMUNOLOGY, 7(10). doi:10.1080/2162402X.2018.1490855

2017

Michaels, A. D., Newhook, T. E., Adair, S. J., Morioka, S., Gaudreau, B. J., Nagdas, S., . . . Bauer, T. W. (2018). CD47 Blockade as an Adjuvant Immunotherapy for Resectable Pancreatic Cancer. CLINICAL CANCER RESEARCH, 24(6), 1415-1425. doi:10.1158/1078-0432.CCR-17-2283

Obeid, J. M., Kunk, P. R., Zaydfudim, V. M., Bullock, T. N., Slingluff, C. L. J., & Rahma, O. E. (2018). Immunotherapy for hepatocellular carcinoma patients: is it ready for prime time?. CANCER IMMUNOLOGY IMMUNOTHERAPY, 67(2), 161-174. doi:10.1007/s00262-017-2082-z

Bullock, T. N. J. (2017). TNF-receptor superfamily agonists as molecular adjuvants for cancer vaccines. CURRENT OPINION IN IMMUNOLOGY, 47, 70-77. doi:10.1016/j.coi.2017.07.005

Siska, P. J., Beckermann, K. E., Mason, F. M., Andrejeva, G., Greenplate, A. R., Sendor, A. B., . . . Rathmell, J. C. (2017). Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. JCI INSIGHT, 2(12). doi:10.1172/jci.insight.93411

Seki, S. M., Stevenson, M., Rosen, A. M., Arandjelovic, S., Gemta, L., Bullock, T. N. J., & Gaultier, A. (2017). Lineage-Specific Metabolic Properties and Vulnerabilities of T Cells in the Demyelinating Central Nervous System. JOURNAL OF IMMUNOLOGY, 198(12), 4607-4617. doi:10.4049/jimmunol.1600825

Burris, H. A., Infante, J. R., Ansell, S. M., Nemunaitis, J. J., Weiss, G. R., Villalobos, V. M., . . . Bullock, T. (2017). Safety and Activity of Varlilumab, a Novel and First-in-Class Agonist Anti-CD27 Antibody, in Patients With Advanced Solid Tumors. JOURNAL OF CLINICAL ONCOLOGY, 35(18), 2028-+. doi:10.1200/JCO.2016.70.1508

Bullock, T. N. J. (2017). Stimulating CD27 to quantitatively and qualitatively shape adaptive immunity to cancer. CURRENT OPINION IN IMMUNOLOGY, 45, 82-88. doi:10.1016/j.coi.2017.02.001

Dill, E. A., Gru, A. A., Atkins, K. A., Friedman, L. A., Moore, M. E., Bullock, T. N., . . . Mills, A. M. (2017). PD-L1 Expression and Intratumoral Heterogeneity Across Breast Cancer Subtypes and Stages An Assessment of 245 Primary and 40 Metastatic Tumors. AMERICAN JOURNAL OF SURGICAL PATHOLOGY, 41(3), 334-342. doi:10.1097/PAS.0000000000000780

Curley, C. T., Sheybani, N. D., Bullock, T. N., & Price, R. J. (2017). Focused Ultrasound Immunotherapy for Central Nervous System Pathologies: Challenges and Opportunities. THERANOSTICS, 7(15), 3608-3623. doi:10.7150/thno.21225

2016

Teoh, J. J., Gamache, A. E., Gillespie, A. L., Stadnisky, M. D., Yagita, H., Bullock, T. N. J., & Brown, M. G. (2016). Acute Virus Control Mediated by Licensed NK Cells Sets Primary CD8+ T Cell Dependence on CD27 Costimulation.. Journal of immunology (Baltimore, Md. : 1950), 197(11), 4360-4370. doi:10.4049/jimmunol.1601049

Obeid, J. M., Erdag, G., Smolkin, M. E., Deacon, D. H., Patterson, J. W., Chen, L., . . . Slingluff, C. L. (2016). PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome. ONCOIMMUNOLOGY, 5(11). doi:10.1080/2162402X.2016.1235107

2015

Dong, H., Franklin, N. A., Ritchea, S. B., Yagita, H., Glennie, M. J., & Bullock, T. N. J. (2015). CD70 and IFN-1 selectively induce eomesodermin or T-bet and synergize to promote CD8+ T-cell responses. EUROPEAN JOURNAL OF IMMUNOLOGY, 45(12), 3289-3301. doi:10.1002/eji.201445291

Bullock, T. (2015). Editorial: Resident good? Persistent infection increases the number of potentially protective T cells localized in peripheral tissue. JOURNAL OF LEUKOCYTE BIOLOGY, 97(2), 211-213. doi:10.1189/jlb.1CE0914-422R

2014

Bullock, T. N. J. (2014). IL-27 and the generation of CD8+ T-cell responses to peptide vaccines. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 111(47), 16639-16640. doi:10.1073/pnas.1418297111

Infante, J. R., Burris, H. A., Ansell, S. M., Nemunaitis, J. J., Weiss, G. R., Villalobos, V. M., . . . Bullock, T. (2014). Immunologic activity of an activating anti-CD27 antibody (CDX-1127) in patients (pts) with solid tumors.. Journal of Clinical Oncology, 32(15_suppl), 3027. doi:10.1200/jco.2014.32.15_suppl.3027

Bullock, T., McClintic, H., Jeong, S., Smith, K., Olson, W., Ramakrishna, V., . . . Keler, T. (2014). Immune correlates of Varlilumab treated cancer patients are consistent with CD27 costimulatory activity. Journal for ImmunoTherapy of Cancer, 2(Suppl 3), P100. doi:10.1186/2051-1426-2-s3-p100

Dong, H., & Bullock, T. N. J. (2014). Metabolic influences that regulate dendritic cell function in tumors. FRONTIERS IN IMMUNOLOGY, 5. doi:10.3389/fimmu.2014.00024

Hargadon, K. M., & Bullock, T. N. J. (2014). The role of tumor/dendritic cell interactions in the regulation of anti-tumor mmunity: the good, the bad, and the ugly. FRONTIERS IN IMMUNOLOGY, 5. doi:10.3389/fimmu.2014.00178

2013

Burris, H., Ansell, S., Neumanitis, J., Weiss, G., Sikic, B., Northfelt, D., . . . Bullock, T. (2013). A phase I study of an agonist anti-CD27 human antibody (CDX-1127) in patients with advanced hematologic malignancies or solid tumors. Journal for ImmunoTherapy of Cancer, 1(S1). doi:10.1186/2051-1426-1-s1-p127

2012

Bullock, T. N. J. (2012). (CD)40 winks to prevent CD8+ T cell lethargy. JOURNAL OF LEUKOCYTE BIOLOGY, 91(6), 845-848. doi:10.1189/jlb.1211650

Dong, H., Franklin, N. A., Roberts, D. J., Yagita, H., Glennie, M. J., & Bullock, T. N. J. (2012). CD27 Stimulation Promotes the Frequency of IL-7 Receptor-Expressing Memory Precursors and Prevents IL-12-Mediated Loss of CD8+ T Cell Memory in the Absence of CD4+ T Cell Help. JOURNAL OF IMMUNOLOGY, 188(8), 3829-3838. doi:10.4049/jimmunol.1103329

2011

Stadnisky, M. D., Xie, X., Coats, E. R., Bullock, T. N., & Brown, M. G. (2011). Self MHC class I-licensed NK cells enhance adaptive CD8 T-cell viral immunity. BLOOD, 117(19), 5133-5141. doi:10.1182/blood-2010-12-324632

2010

Roberts, D. J., Franklin, N. A., Kingeter, L. M., Yagita, H., Tutt, A. L., Glennie, M. J., & Bullock, T. N. J. (2010). Control of Established Melanoma by CD27 Stimulation Is Associated With Enhanced Effector Function and Persistence, and Reduced PD-1 Expression of Tumor Infiltrating CD8+ T Cells. JOURNAL OF IMMUNOTHERAPY, 33(8), 769-779. doi:10.1097/CJI.0b013e3181ee238f