Associate Professor of Medicine
Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine
Member of the Duke Cancer Institute
Duke Cancer Institute
School of Medicine
Affiliate of the Regeneration Next Initiative
Regeneration Next Initiative
School of Medicine
Sun Yat Sen University (China)
Stanford University School of Medicine
Tracing Tumor Evolution in Sarcoma Reveals Clonal Origin of Advanced Metastasis.
Cellular heterogeneity is frequently observed in cancer, but the biological significance of heterogeneous tumor clones is not well defined. Using multicolor reporters and CRISPR-Cas9 barcoding, we trace clonal dynamics in a mouse model of sarcoma. We show that primary tumor growth is associated with a reduction in clonal heterogeneity. Local recurrence of tumors following surgery or radiation therapy is driven by multiple clones. In contrast, advanced metastasis to the lungs is driven by clonal selection of a single metastatic clone (MC). Using RNA sequencing (RNA-seq) and in vivo assays, we identify candidate suppressors of metastasis, namely, Rasd1, Reck, and Aldh1a2. These genes are downregulated in MCs of the primary tumors prior to the formation of metastases. Overexpression of these suppressors of metastasis impair the ability of sarcoma cells to colonize the lungs. Overall, this study reveals clonal dynamics during each step of tumor progression, from initiation to growth, recurrence, and distant metastasis.
Tang, Yuning J., et al. “Tracing Tumor Evolution in Sarcoma Reveals Clonal Origin of Advanced Metastasis.” Cell Rep, vol. 28, no. 11, Sept. 2019, pp. 2837-2850.e5. Pubmed, doi:10.1016/j.celrep.2019.08.029.
Allospecific CD4(+) effector memory T cells do not induce graft-versus-host disease in mice.
We studied whether allospecific CD4(+) effector memory T cells (T(EM)) could induce graft-versus-host disease (GVHD) using a novel GVHD model induced solely by CD4(+) T cell receptor transgenic TEa cells. Allospecific T(EM) generated in a lymphopenic host bore a typical memory phenotype. Moreover, these cells were able to elicit a faster and more effective proliferative response on challenge with alloantigen in vitro and to mediate "second-set" skin graft rejection in vivo. However, these allospecific T(EM) were unable to induce GVHD. Allospecific T(EM) recipients became tolerant to alloantigen as a result of clonal deletion. Even though allospecific T(EM) were able to respond to alloantigen initially, the expansion of these cells and inflammatory cytokine production during GVHD were dramatically decreased. The inability of allospecific T(EM) to sustain the alloresponse may be a result of enhanced activation-induced cell death. These observations provide insight into how allospecific CD4(+) T(EM) respond to alloantigen during GVHD and underscore the fundamental differences in alloresponses mediated by allospecific T(EM) in graft rejection and GVHD settings.
Zhang, Ping, et al. “Allospecific CD4(+) effector memory T cells do not induce graft-versus-host disease in mice.” Biol Blood Marrow Transplant, vol. 18, no. 10, Oct. 2012, pp. 1488–99. Pubmed, doi:10.1016/j.bbmt.2012.07.009.
Biol Blood Marrow Transplant
Treg-cell expansion: Better to be "naive"
Chen, B. J. “Treg-cell expansion: Better to be "naive".” Blood, vol. 108, no. 13, Dec. 2006, pp. 3963–64. Scopus, doi:10.1182/blood-2006-09-048447.
Mechanisms of tolerance induced by PG490-88 in a bone marrow transplantation model
PG490-88 is a semisyntheüc derivative of a novel compound PG490 (triptolide) purified from a Chinese herb (Tripterygium Wilfordii Hook F). Host specific tolerance in vivo was demonstrated in PG490-88-treated BALB/c recipients (H2d, Mls-21, Mls-3") of bone marrow and spleen cells from B10.D2 mice (H2d, Mls-2", Mls-3") by transplantation of recipient or third party neonatal hearts into the pinna of the ears of recipients. The mechanisms of tolerance were studied further in this model. Since all Vβ3 T cells, which recognize the superantigens Mls-2 and Mls-3 and are present in donor B l O.D2 mice but not in recipient BALB/c mice, are activated and cause GVHD in BALB/c recipients, all Vβ3+ T cells are considered host reactive T cells in this model. Therefore, the roles of clonal deletion/anergy can be studied by following the fate of Vβ3 T cells. As shown in the figure, significant numbers of host reactive Vβ3 CD4+ T cells (3.56+1.66 %), which were significant higher than those in normal BALB/c mice (0.27±0.12, P<0.0001) and were comparable with those in normal B l O.D2 mice (6.18±0.51, P>0.05), were present in PG490-88-treated mice. Simulât results were obtained on CD8 T cells. t r(Figure Presented) 6 NomulBALWc 5 OT-d«plet»d bone marrow T 4 OPG49M8 I I 3 ONwrnil BIO D2 BH These results suggest that clonal deletion was not responsible for the observed tolerance induced by PG490-88, In contrast, Vβ3- T cells were completely deleted in the control Tdepleted bone marrow recipients. Vβ3 T cells obtained from PG490-88-treated recipients which were demonstrated to be tolerant to host antigens proliferated normally in response to T cell receptor crosslinking mediated by anti-CD3 antibody. Neither antigen specific nor antigen nonspecific suppressor cells were found in PG490-88-treated mice. Taken together, the host specific tolerance induced by PG490-88 in a murine BMT model is not due to deletion of alloreactive cells. Moreover, suppressor cells are not involved in the maintenance of tolerance. Rather, PG490-88 appears to lead to allotolerance through the induction of a state of antigen specific anergy of the responding T cells.
Chen, BJ; Cui, X; Fidler, JM; Chao, NJ
Chen, B. J., et al. “Mechanisms of tolerance induced by PG490-88 in a bone marrow transplantation model.” Blood, vol. 96, no. 11 PART II, Dec. 2000.
CD62L- memory T cells enhance T-cell regeneration after allogeneic stem cell transplantation by eliminating host resistance in mice.
A major challenge in allogeneic hematopoietic cell transplantation is how to transfer T-cell immunity without causing graft-versus-host disease (GVHD). Effector memory T cells (CD62L(-)) are a cell subset that can potentially address this challenge because they do not induce GVHD. Here, we investigated how CD62L(-) T cells contributed to phenotypic and functional T-cell reconstitution after transplantation. On transfer into allogeneic recipients, CD62L(-) T cells were activated and expressed multiple cytokines and cytotoxic molecules. CD62L(-) T cells were able to deplete host radioresistant T cells and facilitate hematopoietic engraftment, resulting in enhanced de novo T-cell regeneration. Enhanced functional immune reconstitution was demonstrated in CD62L(-) T-cell recipients using a tumor and an influenza virus challenge model. Even though CD62L(-) T cells are able to respond to alloantigens and deplete host radioresistant immune cells in GVHD recipients, alloreactive CD62L(-) T cells lost the reactivity over time and were eventually tolerant to alloantigens as a result of prolonged antigen exposure, suggesting a mechanism by which CD62L(-) T cells were able to eliminate host resistance without causing GVHD. These data further highlight the unique characteristics of CD62L(-) T cells and their potential applications in clinical hematopoietic cell transplantation.
Zhang, J; Barefoot, BE; Mo, W; Deoliveira, D; Son, J; Cui, X; Ramsburg, E; Chen, BJ
Zhang, Jifeng, et al. “CD62L- memory T cells enhance T-cell regeneration after allogeneic stem cell transplantation by eliminating host resistance in mice.” Blood, vol. 119, no. 26, June 2012, pp. 6344–53. Pubmed, doi:10.1182/blood-2011-03-342055.
Anti-Inflammatory Agents, Non-Steroidal
Antineoplastic Agents, Alkylating
Blood Cell Count
Bone Marrow Cells
Bone Marrow Purging
Bone Marrow Transplantation
Colony-Forming Units Assay
Disease Models, Animal
Drugs, Chinese Herbal
Graft vs Host Disease
Graft vs Leukemia Effect
Graft vs Tumor Effect
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells
Mice, Inbred BALB C
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Inbred MRL lpr
Radiation Injuries, Experimental
Receptor, Angiotensin, Type 1
Receptors, Antigen, T-Cell
Recovery of Function
Reproducibility of Results
Specific Pathogen-Free Organisms
Stem Cell Transplantation
Toll-Like Receptor 4
Tumor Cells, Cultured
Associate Professor of Medicine
Box 103866 Med Ctr, Durham, NC 27710
GSRB1 Rm 4004B, 905 S Lasalle Street, Durham, NC 27710