Emmanuel Katsanis

Emmanuel Katsanis, MD, recognizes immunity against tumors depends on complex innate and adaptive immune responses that involve the sequential mobilization of messenger and killer immune cells. However, despite the arsenal harbored by the immune system to ensure tumor immunosurveillance, cancers can escape immune detection and elimination. Dr. Katsanis’ lab conducts a basic and translational research program aimed at advancing new immunotherapeutic strategies as a cure for cancer. They are specifically focusing on deciphering the phenomena of tumor-induced immunosuppression and are investigating approaches to override their negative impact on antitumoral immunity. A concomitant and complementary area of research centers on the optimization and development of cancer vaccines and on the identification of novel cellular actors of the immune system that may be manipulated to control malignancies. This two-step strategy converges toward the promotion of tightly orchestrated tumor-specific immune responses. The primary research areas in our laboratory are the following: 1) mechanisms of tumor-induced immunosuppression and 2) promotion of anti-tumor immunity.
The research is exploring additional therapeutic approaches to eliminate or inactivate tumor-induced Treg and is also pursuing the study of the mechanisms leading to the induction and regulation of their immunosuppressive function.
Myeloid-derived suppressor cells (MDSC) contribute to tumor-induced immunosuppression. The number of these cells is increased in tumor-bearing hosts and they may specifically or non- specifically suppress immunity by mechanisms involving arginase-1, reactive oxygen and nitrogen species. In mice MDSC express the CD11b and Gr-1 markers and may be involved in the generation of Treg. A project has been initiated and aimed at evaluating the role and modality of induction of these cells in cancer and at exploring the reciprocal interaction between tumor-induced MDSC and Treg.
Cytotoxic And Antigen Presenting Functions Of T Helper 1 Activated Dendritic Cells. Source: Oncoimmunology
September 14th, 2012 PMID: 22754789 Emmanuel Katsanis
Although primarily defined by their cardinal antigen-presenting function, dendritic cells (DCs) are also equipped with cytotoxic properties. We have recently reported that DCs activated by IFNγ-secreting Th-1 lymphocytes can kill cancer cells and subsequently present the acquired tumor-derived antigens to T lymphocytes both in vitro and in vivo.<br /><br />
Myeloid Derived Suppressor Cells From Tumor Bearing Mice Impair Tgf β Induced Differentiation Of Cd4+Cd25+Fox P3+ Tregs From Cd4+Cd25 Fox P3 T Cells. Source: Journal Of Leukocyte Biology
August 13th, 2012 PMID: 22891289 Emmanuel Katsanis
MDSCs and Tregs play an essential role in the immunosuppressive networks that contribute to tumor-immune evasion. The mechanisms by which tumors promote the expansion and/or function of these suppressive cells and the cross-talk between MDSC and Treg remain incompletely defined. Previous reports have suggested that MDSC may contribute to Treg induction in cancer. Herein, we provide evidence that tumor-induced gr-MDSCs, endowed with the potential of suppressing conventional T Lc, surprisingly impair TGF-β1-mediated generation of CD4(+)CD25(+)FoxP3(+) iTregs. Furthermore, gr-MDSCs impede the proliferation of nTregs without, however, affecting FoxP3 expression. Suppression of iTreg differentiation from naïve CD4(+) cells by gr-MDSC occurs early in the polarization process, requires inhibition of early T cell activation, and depends on ROS and IDO but does not require arginase 1, iNOS, NO, cystine/cysteine depletion, PD-1 and PD-L1 signaling, or COX-2. These findings thus indicate that gr-MDSCs from TB hosts have the unanticipated ability to restrict immunosuppressive Tregs.<br /><br />
Th 1 Lymphocytes Induce Dendritic Cell Tumor Killing Activity By An Ifn γ Dependent Mechanism. Source: Journal Of Immunology (Baltimore, Md. : 1950)
November 9th, 2011 PMID: 22075702 Emmanuel Katsanis
Dendritic cells (DCs) encompass a heterogeneous population of cells capable of orchestrating innate and adaptive immune responses. The ability of DCs to act as professional APCs has been the foundation for the development and use of these cells as vaccines in cancer immunotherapy. DCs are also endowed with the nonconventional property of directly killing tumor cells. The current study investigates the regulation of murine DC cytotoxic function by T lymphocytes. We provide evidence that CD4(+) Th-1, but not Th-2, Th-17 cells, or regulatory T cells, are capable of inducing DC cytotoxic function. IFN-γ was identified as the major factor responsible for Th-1-induced DC tumoricidal activity. Tumor cell killing mediated by Th-1-activated killer DCs was dependent on inducible NO synthase expression and NO production. Importantly, Th-1-activated killer DCs were capable of presenting the acquired Ags from the killed tumor cells to T lymphocytes in vitro or in vivo. These observations offer new possibilities for the application of killer DCs in cancer immunotherapy.<br /><br />
Allogeneic Effector/Memory Th 1 Cells Impair Fox P3+ Regulatory T Lymphocytes And Synergize With Chaperone Rich Cell Lysate Vaccine To Treat Leukemia. Source: Blood
December 1st, 2010 PMID: 21123824 Emmanuel Katsanis
Therapeutic strategies combining the induction of effective antitumor immunity with the inhibition of the mechanisms of tumor-induced immunosuppression represent a key objective in cancer immunotherapy. Herein we demonstrate that effector/memory CD4(+) T helper-1 (Th-1) lymphocytes, in addition to polarizing type-1 antitumor immune responses, impair tumor-induced CD4(+)CD25(+)FoxP3(+) regulatory T lymphocyte (Treg) immunosuppressive function in vitro and in vivo. Th-1 cells also inhibit the generation of FoxP3(+) Tregs from naive CD4(+)CD25(-)FoxP3(-) T cells by an interferon-γ-dependent mechanism. In addition, in an aggressive mouse leukemia model (12B1), Th-1 lymphocytes act synergistically with a chaperone-rich cell lysate (CRCL) vaccine, leading to improved survival and long-lasting protection against leukemia. The combination of CRCL as a source of tumor-specific antigens and Th-1 lymphocytes as an adjuvant has the potential to stimulate efficient specific antitumor immunity while restraining Treg-induced suppression.<br><br>
Signaling Pathways Induced By A Tumor Derived Vaccine In Antigen Presenting Cells. Source: Immunobiology
October 31st, 2009 PMID: 19880213 Emmanuel Katsanis
We have previously reported on the anti-tumoral potential of a chaperone-rich cell lysate (CRCL) vaccine. Immunization with CRCL generated from tumors elicits specific T and NK cell-dependent immune responses leading to protective immunity in numerous mouse tumor models. CRCL provides both a source of tumor antigens and danger signals leading to dendritic cell activation. In humans, tumor-derived CRCL induces dendritic cell activation and CRCL-loaded dendritic cells promote the generation of cytotoxic T lymphocytes in vitro. The current study was designed to identify the signaling events and modifications triggered by CRCL in antigen presenting cells. Our results indicate that tumor-derived CRCL not only promotes the activation of dendritic cells, but also significantly fosters the function of macrophages that thus appear as major targets of this vaccine. Activation of both cell types is associated with the induction of the MAP kinase pathway, the phosphorylation of STAT1, STAT5 and AKT and with transcription factor NF-kappaB activation in vitro and in vivo. These results thus provide important insights into the mechanisms by which CRCL-based vaccines exert their adjuvant effects on antigen presenting cells.<br /><br />
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