Gang Zhou

Georgia Health Sciences University, Augusta, GA, United States

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Publications (13)107.23 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: In recent years, immune-based therapies have become an increasingly attractive treatment option for patients with cancer. Cancer immunotherapy is often used in combination with conventional chemotherapy for synergistic effects. The alkylating agent cyclophosphamide (CTX) has been included in various chemoimmunotherapy regimens due to its well-known immunostimulatory effects. Paradoxically, CTX can also induce suppressor cells that inhibit immune responses. However, the identity and biological relevance of these suppressor cells are poorly defined. Here we report that CTX treatment drives the expansion of inflammatory monocytic myeloid cells (CD11b+Ly6ChiCCR2hi) that possess immunosuppressive activities. In mice with advanced lymphoma, adoptive transfer (AT) of tumor-specific CD4+ T cells following CTX treatment (CTX+CD4 AT) provoked a robust initial antitumor immune response, but also resulted in enhanced expansion of monocytic myeloid cells. These therapy-induced monocytes inhibited long-term tumor control and allowed subsequent relapse by mediating functional tolerization of antitumor CD4+ effector cells through the PD-1/PD-L1 axis. PD-1/PD-L1 blockade after CTX+CD4 AT therapy led to persistence of CD4+ effector cells and durable antitumor effects. Depleting proliferative monocytes by administering low dose gemcitabine effectively prevented tumor recurrence after CTX+CD4 AT therapy. Likewise, targeting inflammatory monocytes by disrupting the CCR2 signaling pathway markedly potentiated the efficacy of CTX-based therapy. Besides CTX, we found that melphalan and doxorubicin can also induce monocytic myeloid suppressor cells. These findings reveal a counter-regulation mechanism elicited by certain chemotherapeutic agents, and highlight the importance of overcoming this barrier to prevent late tumor relapse after chemoimmunotherapy.
    Cancer Research 04/2014; · 9.28 Impact Factor
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    ABSTRACT: The finding that many chemotherapeutic agents have immunostimulatory effects has provided the impetus to combine chemotherapy and immunotherapy for synergistic antitumor effects. However, the critical determinants of effective antitumor immunity after chemotherapy have not been defined. Here we report that adoptive transfer of tumor-specific CD4(+) T cells after chemotherapy with cyclophosphamide gave rise to polyfunctional CD4(+) effector cells, which in turn intensified the inflammatory milieu and enhanced the activation of CD8(+) T cells in the tumor microenvironment. Although this combined chemoimmunotherapy initially resulted in progressive regression of advanced B-cell lymphoma, its therapeutic efficacy was not durable and most mice succumbed to late relapse. Notably, relapse was associated with acquisition of a tolerized phenotype in tumor-specific CD4(+) T cells, characterized by overexpression of program death-1 (PD-1). Remarkably, effective antitumor immunity was maintained and cure became prevalent when polyfunctional CD4(+) effector cells were prevented from undergoing PD-1-mediated tolerization, either by antibody blockade of the PD-1-PD-L1 pathway, or targeted ablation of PD-1 in tumor-specific CD4(+) T cells. Our study suggests that tumor-reactive CD4(+) T cells act as the "gatekeepers" of the host antitumor immunity in the postchemotherapy setting, thereby their functional status governs the choice between eradication versus regrowth of residual tumors.
    Blood 08/2012; 120(11):2229-39. · 9.78 Impact Factor
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    Gang Zhou, Hyam Levitsky
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    ABSTRACT: The past decade has witnessed the evolvement of cancer immunotherapy as an increasingly effective therapeutic modality, evidenced by the approval of two immune-based products by the FDA, that is, the cancer vaccine Provenge (sipuleucel-T) for prostate cancer and the antagonist antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4) ipilimumab for advanced melanoma. In addition, the clinical evaluations of a variety of promising immunotherapy drugs are well under way. Benefiting from more efficacious immunotherapeutic agents and treatment strategies, a number of recent clinical studies have achieved unprecedented therapeutic outcomes in some patients with certain types of cancers. Despite these advances, however, the efficacy of most cancer immunotherapies currently under clinical development has been modest. A recurring scenario is that therapeutic maneuvers initially led to measurable antitumor immune responses in cancer patients but ultimately failed to improve patient outcomes. It is increasingly recognized that tumor cells can antagonize therapy-induced immune attacks through a variety of counterregulation mechanisms, which represent a fundamental barrier to the success of cancer immunotherapy. Herein we summarize the findings from some recent preclinical and clinical studies, focusing on how tumor cells advance their survival and expansion by hijacking therapy-induced immune effector mechanisms that would otherwise mediate their destruction.
    Clinical and Developmental Immunology 01/2012; 2012:124187. · 3.06 Impact Factor
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    Zhi-Chun Ding, Gang Zhou
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    ABSTRACT: Standard cytotoxic chemotherapy can initially achieve high response rates, but relapses often occur in patients and represent a severe clinical problem. As increasing numbers of chemotherapeutic agents are found to have immunostimulatory effects, there is a growing interest to combine chemotherapy and immunotherapy for synergistic antitumor effects and improved clinical benefits. Findings from recent studies suggest that highly activated, polyfunctional CD4+ effector T cells have tremendous potential in strengthening and sustaining the overall host antitumor immunity in the postchemotherapy window. This review focuses on the latest progresses regarding the impact of chemotherapy on CD4+ T-cell phenotype and function and discusses the prospect of exploiting CD4+ T cells to control tumor progression and prevent relapse after chemotherapy.
    Clinical and Developmental Immunology 01/2012; 2012:890178. · 3.06 Impact Factor
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    ABSTRACT: Activated T cells can acquire membrane molecules from APCs through a process termed trogocytosis. The functional consequence of this event has been a subject of debate. Focusing on transfer of peptide-MHC class II (MHC-II) complexes from APCs to CD4(+) T cells after activation, in this study we investigated the molecule acquisition potential of naturally occurring regulatory T cells (Tregs) and CD4(+) Th cells. We show that acquisition of membrane molecules from APCs is an inherent feature of CD4(+) T cell activation. Triggering of the TCR enables CD4(+) T cells to acquire their agonist ligands as well as other irrelevant membrane molecules from the interacting APCs or bystander cells in a contact-dependent manner. Notably, trogocytosis is a continuous process during cell cycle progression, and Th cells and Tregs have comparable capacity for trogocytosis both in vitro and in vivo. The captured peptide-MHC-II molecules, residing in sequestered foci on the host cell surface, endow the host cells with Ag-presenting capability. Presentation of acquired peptide-MHC-II ligands by Th cells or Tregs has either stimulatory or regulatory effect on naive CD4(+) T cells, respectively. Furthermore, Th cells with captured peptide-MHC-II molecules become effector cells that manifest better recall responses, and Tregs with captured ligands exhibit enhanced suppression activity. These findings implicate trogocytosis in different subsets of CD4(+) T cells as an intrinsic mechanism for the fine tuning of Ag-specific CD4(+) T cell response.
    The Journal of Immunology 02/2011; 186(4):2148-55. · 5.52 Impact Factor
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    ABSTRACT: The functional development of tumor-specific CD4(+) T cells has a critical impact on the outcome of antitumor immune responses. Adoptive immunotherapy involving tumor-specific CD4(+) T cells has shown encouraging clinical benefits in some cancer patients. To mount an effective antitumor immunity, it is desirable to elicit activated type 1 T helper cells. Here, we report that type 1 T helper cell-like effector cells that arose in tumor-bearing hosts progressively expressed programmed death 1 during tumor growth. The programmed death 1(hi) effector cells displayed a dysfunctional phenotype, characterized by selective down-regulation of interleukin-7 receptor, heightened apoptosis, and poor antitumor efficacy. This tumor-driven aberrant T-cell response could be prevented by a single dose of the widely used chemotherapy agent cyclophosphamide. We show that chemotherapy conditioned the host environment, creating a transient window for optimal effector differentiation for adoptively transferred CD4(+) T cells. This robust effector differentiation, which was antigen-driven and mechanistically dependent on an intact host response to type I interferon, gave rise to activated polyfunctional T helper cells with high interleukin-7 receptor, rapid clonal expansion, and potent antitumor activity against established B-cell lymphomas. We hypothesize that prevention of tumor-induced effector cell dysfunction is a major mechanism contributing to the efficacy of combined chemoimmunotherapy.
    Blood 03/2010; 115(12):2397-406. · 9.78 Impact Factor
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    ABSTRACT: The "allogeneic effect" refers to the induction of host B cell antibody synthesis or host T cell cytotoxicity, including tumoricidal activity, by an infusion of allogeneic lymphocytes. We show that treatment of mice with cyclophosphamide (Cy) followed by CD8(+) T cell-depleted allogeneic donor lymphocyte infusion (Cy + CD8(-) DLI) induces regression of established tumors with minimal toxicity in models of both hematologic and solid cancers, even though the donor cells are eventually rejected by the host immune system. The optimal antitumor effect of Cy + CD8(-) DLI required the presence of donor CD4(+) T cells, host CD8(+) T cells, and alloantigen expression by normal host but not tumor tissue. The results support a model in which a donor CD4(+) T cell-mediated graft-versus-host (GVH) reaction effectively awakens antitumor immunity among Cy-resistant host CD8(+) T cells. These events provide the cellular mechanism of the "allogeneic effect" in antitumor immunity. Cy + CD8(-) DLI may be an effective and minimally toxic strategy for awakening the host immune response to advanced cancers.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 06/2008; 14(5):499-509. · 3.15 Impact Factor
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    ABSTRACT: Immune reconstitution of autologous hematopoietic stem-cell transplant recipients with the progeny of mature T cells in the graft leads to profound changes in the emerging functional T-cell repertoire. In the steady state, the host is frequently tolerant to tumor antigens, reflecting dominant suppression of naive and effector T cells by regulatory T cells (T(regs)). We examined the relative frequency and function of these 3 components within the tumor-specific T-cell compartment during immune reconstitution. Grafts from tumor-bearing donors exerted a significant antitumor effect in irradiated, syngeneic tumor-bearing recipients. This was associated with dramatic clonal expansion and interferon-gamma (IFNgamma) production by previously tolerant tumor-specific T cells. While donor-derived T(regs) expanded in recipients, they did not inhibit the antigen-driven expansion of effector T cells in the early posttransplantation period. Indeed, the repopulation of tumor-specific effector T cells significantly exceeded that of T(regs), the expansion of which was limited by IL-2 availability. Although the intrinsic suppressive capacity of T(regs) remained intact, their diminished frequency was insufficient to suppress effector cell function. These findings provide an explanation for the reversal of tolerance leading to tumor rejection in transplant recipients and likely contribute to the efficacy of adoptive T-cell therapies in lymphopenic hosts.
    Blood 03/2008; 111(4):2112-21. · 9.78 Impact Factor
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    Gang Zhou, Hyam I Levitsky
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    ABSTRACT: Thymus-derived, naturally occurring CD4(+)CD25(+)Foxp3(+) regulatory T cells (nTregs) and Tregs induced in the periphery (iTregs) have both been implicated in regulating immune responses. However, the relationship between these populations in the same host, and their relative contribution to the overall Treg pool, has not been examined. Using a tumor-induced T cell tolerance model, we find that expansion of nTregs and de novo generation of iTregs both contribute to tumor-specific T cell tolerance. In this system in which the number of tumor-specific nTregs can be controlled, the efficiency of nTreg expansion significantly exceeds that of the induction of Tregs from uncommitted progenitors in the tumor-bearing host. However, pre-existing nTregs are neither required for the induction of Tregs nor measurably impact on the extent of their accumulation. Instead, induction of Ag-specific regulatory cells from naive cells is intrinsically influenced by the tumor microenvironment and the presence of tumor Ag.
    The Journal of Immunology 03/2007; 178(4):2155-62. · 5.52 Impact Factor
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    ABSTRACT: The fate of tumor-specific CD4(+) T cells is central to the outcome of the host immune response to cancer. We show that tumor antigen recognition by a subset of CD4(+) T cells led to their differentiation into cells capable of suppressing naive and Th1 effector cells. Such tumor-induced regulatory T cells (TMTregs) arose both from precommitted "natural" regulatory T cells and CD4(+)CD25(-)GITR(low) precursors. Once induced, TMTregs were capable of maintaining suppressor activity long after transfer into antigen-free recipients. Suppression was mediated by GITR(high) cells residing within both CD25(+) and CD25(-) subsets. Vaccination of the tumor-bearing host concomitantly expanded TMTregs and effector cells, but suppression was dominant, blunting the expansion of naive tumor-specific T cells and blocking the execution of effector function in vitro and in vivo. These studies illustrate the possibility that therapeutic vaccination could actually worsen host tolerance to tumor antigens and support treatment paradigms that seek to not only increase the frequency of tumor-specific T cells, but to do so in conjunction with strategies that inactivate or remove regulatory T-cell populations.
    Blood 02/2006; 107(2):628-36. · 9.78 Impact Factor
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    ABSTRACT: Two seemingly incompatible models exist to explain the progression of cancers in immunocompetent hosts. The cancer immunosurveillance hypothesis posits that recognition of transformed cells by the immune system results in the generation of an effector response that may impede tumor growth. Clinically detectable cancer results from the emergence of tumor variants that escape this selective pressure. Alternatively, induction of immune tolerance to tumor antigens may enable cancer progression. We established a model where changes in the function of tumor-specific T cells and in tumor antigen expression could be followed during cancer progression. Early recognition of antigen led to activation, expansion, and effector function in tumor-specific CD4+ T cells resulting in the outgrowth of tumors expressing substantially reduced levels of antigen. Antigen loss was not complete, however, and levels remained above the threshold required for tumor-specific T cell recognition in vivo. In the face of persisting antigen, T cell tolerance ensued, leading to an impaired ability to mediate further antigen loss. Together, these studies establish that the processes of immunosurveillance and tumor editing coexist with a process in which the functional tumor-specific T cell repertoire is also "edited," reconciling two hypotheses historically central to our attempts to understand host antitumor immunity.
    Journal of Experimental Medicine 01/2005; 200(12):1581-92. · 13.21 Impact Factor
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    ABSTRACT: Regulatory T cells (Tregs) limit autoimmunity but also attenuate the magnitude of antipathogen and antitumor immunity. Understanding the mechanism of Treg function and therapeutic manipulation of Tregs in vivo requires identification of Treg-selective receptors. A comparative analysis of gene expression arrays from antigen-specific CD4(+) T cells differentiating to either an effector/memory or a regulatory phenotype revealed Treg-selective expression of LAG-3, a CD4-related molecule that binds MHC class II. Antibodies to LAG-3 inhibit suppression by induced Tregs both in vitro and in vivo. Natural CD4(+)CD25(+) Tregs express LAG-3 upon activation, which is significantly enhanced in the presence of effector cells, whereas CD4(+)CD25(+) Tregs from LAG-3(-/-) mice exhibit reduced regulatory activity. Lastly, ectopic expression of LAG-3 on CD4(+) T cells significantly reduces their proliferative capacity and confers on them suppressor activity toward effector T cells. We propose that LAG-3 marks regulatory T cell populations and contributes to their suppressor activity.
    Immunity 11/2004; 21(4):503-13. · 19.80 Impact Factor
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    ABSTRACT: An important process in the generation of tolerance to peripheral self-Ags is the induction of unresponsiveness in mature specific T cells. Although the end stage of this process, termed anergy, is well defined, the pathway by which naive T cells become anergic remains to be elucidated. Using an in vivo self-tolerance model, we demonstrate that CD4(+) T cells pass through a significant effector stage on their way to an anergic state. This stage is characterized by production of effector cytokines, provision of help for CD8(+) T cells, and induction of in vivo pathology within organs that express cognate Ag. These results suggest that the initial activation stage in T cell tolerance is similar to that seen in memory induction. They also suggest that autoimmune pathology can result during the natural process of tolerance induction rather than requiring that tolerance be broken.
    The Journal of Immunology 05/2003; 170(8):3945-53. · 5.52 Impact Factor

Publication Stats

724 Citations
107.23 Total Impact Points

Institutions

  • 2010–2012
    • Georgia Health Sciences University
      • Cancer Center
      Augusta, GA, United States
  • 2007–2008
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
  • 2005
    • Johns Hopkins University
      Baltimore, Maryland, United States