Timothy N. Bullock
- Email: email@example.com
- Phone: 434-982-1932
- Fax: 434-924-9824
Associate Professor, Pathology
- PhD, Thomas Jefferson University
Cancer Biology, Experimental Pathology, Immunology, Infectious Diseases/Biodefense, Translational Science
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.
Recent studies in our laboratory have indicated that mice immunized with both MHC class I- and class II-restricted peptides derived from an antigen expressed by tumor results in greater control of tumor outgrowth as compared to mice immunized with the MHC class I-restricted peptide alone (Hwang et al, 2007). Further studies have indicated that tumor-specific memory CD4+ T cells enhance the activation, differentiation and, in particular, the infiltration of tumor by secondary CD8+ T cells. As a consequence of this, we are currently studying:
1. Whether the enhanced frequency of tumor-specific CD8+ T cells in the lungs is due to recruitment of central memory CD8+ T cells, or the expansion of effector memory CD8+ T cells. If recruitment is involved, which facets of the memory CD4+ T cells are responsible, and which chemokines and integrins are involved?
2. Is the enhanced activation and differentiation of memory CD8+ T cells due to differential activation of DC by memory CD4+ T cells as compared to naÃ¯ve CD4+ T cells?
3. Whether other parameters of CD8+ T cell function are enhanced by coordinated reactivation with memory CD4+ T cells.
4. What are the qualitative and quantitative aspects of memory CD4+ T cells that support secondary CD8+ T cell responses to tumor?
5. The parameters of immunization that elicit the most potent CD4+ T cell responses, but not to the detriment of the CD8+ T cell response.
6. Whether cognate or non-cognate CD4+ T cell responses are more supportive of tumor control when tumor is already existent in the host.
As a consequence of our interest in how CD4+ T cells influence CD8+ T cell responses to tumor, our lab has also shown that one of the essential consequences of âlicensingâ DC via CD40-mediated stimulation 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 naÃ¯ve T and B cells, and a subset of NK cells) strongly influences both CD8+ T cell and CD4+ T cell responses to DC vaccines. Current projects in the lab involve:
1. Defining the mechanism by which CD4+ T cells induce the expression of CD70 on DC
2. Determine which other methods of stimulating DC induce CD70 expression on DC.
3. Examining how CD70-mediated costimulation influences the expansion and differentiation of both CD8+ T cell and CD4+ T cell responses.
4. Defining how to utilize CD70-mediated costimulation to enhance immunological control of tumor.
As part of our interest in developing effective immune responses against tumors in humans, our lab is currently studying the phenotype and functionality of CD8+ T cell and CD4+ T cell responses elicited by peptide+adjuvant vaccines administered to melanoma and breast cancer patients at the University of Virginia. 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 patientâs T cell response, and whether additional interventions may overcome such deficiencies.
- Biodefense & Infectious Diseases Short-Term Training to Increase Diversity in Biomedical Sciences
- Cancer Research Training in Molecular Biology
- Interdisciplinary Training Program in Immunology
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
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
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
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
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
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
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
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
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
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 T(H)17 cells. SCIENCE SIGNALING, 13(655). doi:10.1126/scisignal.aay9217
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
Wages, N. A., Jr, S. C. L., 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-7R alpha 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-beta Is Required for TNF-alpha 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
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
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
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
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
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
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
Obeid, J. M., Kunk, P. R., Zaydfudim, V. M., Bullock, T. N., Jr, S. C. L., & 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
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
Melssen, M. M., Olson, W., Wages, N. A., Capaldo, B. J., Mauldin, I. S., Mahmutovic, A., . . . Jr, S. C. L. (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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Van Deusen, K. E., Rajapakse, R., & Bullock, T. N. J. (2010). CD70 expression by dendritic cells plays a critical role in the immunogenicity of CD40-independent, CD4(+) T cell-dependent, licensed CD8(+) T cell responses. JOURNAL OF LEUKOCYTE BIOLOGY, 87(3), 477-485. doi:10.1189/jlb.0809535