Emmanuel Katsanis
Professor, BIO5 Institute
Professor, Immunobiology
Professor, Medicine
Professor, Pathology
Professor, Pediatrics
Program Director, Blood and Bone Marrow Transplant
Professor, Cancer Biology - GIDP
Primary Department
Department Affiliations
(520) 626-7053
Work Summary
Augmenting immune responses to cancer. Reducing relapse and graft versus host disease after hematopoietic cell transplantation.
Research Interest
Dr. Emmanuel Katsanis, MD, and his laboratory conduct basic and translational research aimed at advancing new cancer immunotherapeutic strategies. His expertise is in stem cell transplant immunology, cellular therapy, and cancer vaccine approaches.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. Current research in the laboratory is evaluating immuno- and chemo-immunotherapeutic strategies to promote anti-tumor immune responses following bone marrow transplantation, while investigating approaches to mitigate graft versus host effects. Keywords: Cancer Immunology, Hematopoietic Cell Transplantation

Publications

Hanke, N. T., LaCasse, C. J., Larmonier, C. B., Alizadeh, D., Trad, M., Janikashvili, N., Bonnotte, B., Katsanis, E., & Larmonier, N. (2014). PIAS1 and STAT-3 impair the tumoricidal potential of IFN-γ-stimulated mouse dendritic cells generated with IL-15. European journal of immunology, 44(8), 2489-99.

Primarily defined by their antigen-presenting property, dendritic cells (DCs) are being implemented as cancer vaccines in immunotherapeutic interventions. DCs can also function as direct tumor cell killers. How DC cytotoxic activity can be efficiently harnessed and the mechanisms controlling this nonconventional property are not fully understood. We report here that the tumoricidal potential of mouse DCs generated from myeloid precursors with GM-CSF and IL-15 (IL-15 DCs) can be triggered with the Toll-like receptor (TLR) 4 ligand lipopolysaccharide to a similar extent compared with that of their counterparts, conventionally generated with IL-4 (IL-4 DCs). The mechanism of tumor cell killing depends on the induction of iNOS expression by DCs. In contrast, interferon (IFN)-γ induces the cytotoxic activity of IL-4 but not IL-15 DCs. Although the IFN-γ-STAT-1 signaling pathway is overall functional in IL-15 DCs, IFN-γ fails to induce iNOS expression in these cells. iNOS expression is negatively controlled in IFN-γ-stimulated IL-15 DCs by the cooperation between the E3 SUMO ligase PIAS1 and STAT-3, and can be partially restored with PIAS1 siRNA and STAT-3 inhibitors.

Bleifuss, E., Bendz, H., Sirch, B., Thompson, S., Brandl, A., Milani, V., Graner, M. W., Drexler, I., Kuppner, M., Katsanis, E., Noessner, E., & Issels, R. D. (2008). Differential capacity of chaperone-rich lysates in cross-presenting human endogenous and exogenous melanoma differentiation antigens. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group, 24(8), 623-37.

The goal of immune-based tumor therapies is the activation of immune cells reactive against a broad spectrum of tumor-expressed antigens. Vaccines based on chaperone proteins appear promising as these proteins naturally exist as complexes with various protein fragments including those derived from tumor-associated antigens. Multi-chaperone systems are expected to have highest polyvalency as different chaperones can carry distinct sets of antigenic fragments. A free-solution isoelectric focusing (FS-IEF) technique was established to generate chaperone-rich cell lysates (CRCL). Results from murine systems support the contention that CRCL induce superior anti-tumor responses than single chaperone vaccines. We established an in vitro model for human melanoma to evaluate the capacity of CRCL to transfer endogenously expressed tumor antigens to the cross-presentation pathway of dendritic cells (DC) for antigen-specific T cell stimulation. CRCL prepared from human melanoma lines contained the four major chaperone proteins Hsp/Hsc70, Hsp90, Grp94/gp96 and calreticulin. The chaperones within the melanoma cell-derived CRCL were functionally active in that they enhanced cross-presentation of exogenous peptides mixed into the CRCL preparation. Superior activity was observed for Hsp70-rich CRCL obtained from heat-stressed melanoma cells. Despite the presence of active chaperones, melanoma cell-derived CRCL failed to transfer endogenously expressed melanoma-associated antigens to DC for cross-presentation and cytotoxic T cell (CTL) recognition, even after increasing intracellular protein levels of tumor antigen or chaperones. These findings reveal limitations of the CRCL approach regarding cross-presentation of endogenously expressed melanoma-associated antigens. Yet, CRCL may be utilized as vehicles to enhance the delivery of exogenous antigens for DC-mediated cross-presentation and T cell stimulation.

Katsanis, E., Sapp, L. N., Pelayo-Katsanis, L., Whitney, K., Zeng, Y., & Kopp, L. M. (2016). Alternative Donor Hematopoietic Cell Transplantation Conditioned With Myeloablative Busulfan, Fludarabine, and Melphalan is Well Tolerated and Effective Against High-risk Myeloid Malignancies. Journal of pediatric hematology/oncology, 38(8), e315-e318.

Busulfan, fludarabine, and melphalan as hematopoietic cell transplant conditioning, was used in 6 patients aged 1 to 19 years with very high-risk myeloid malignancies. This dose regimen had an acceptable toxicity profile resulting in complete donor engraftment even following transplantation of small 2/6 antigen disparate umbilical cord blood grafts. It provided excellent disease control as all patients had high-risk features in terms of cytogenetics, therapy-related leukemia, and/or significant measurable disease before transplant. All patients remain in remission, without acute or chronic graft-versus-host disease with a median follow-up of 24 months. A larger study is indicated to confirm the efficacy and safety of this regimen.

Fraszczak, J., Trad, M., Janikashvili, N., Cathelin, D., Lakomy, D., Granci, V., Morizot, A., Audia, S., Micheau, O., Lagrost, L., Katsanis, E., Solary, E., Larmonier, N., & Bonnotte, B. (2010). Peroxynitrite-dependent killing of cancer cells and presentation of released tumor antigens by activated dendritic cells. Journal of immunology (Baltimore, Md. : 1950), 184(4), 1876-84.

Dendritic cells (DCs), essential for the initiation and regulation of adaptive immune responses, have been used as anticancer vaccines. DCs may also directly trigger tumor cell death. In the current study, we have investigated the tumoricidal and immunostimulatory activities of mouse bone marrow-derived DCs. Our results indicate that these cells acquire killing capabilities toward tumor cells only when activated with LPS or Pam3Cys-SK4. Using different transgenic mouse models including inducible NO synthase or GP91 knockout mice, we have further established that LPS- or Pam3Cys-SK4-activated DC killing activity involves peroxynitrites. Importantly, after killing of cancer cells, DCs are capable of engulfing dead tumor cell fragments and of presenting tumor Ags to specific T lymphocytes. Thus, upon specific stimulation, mouse bone marrow-derived DCs can directly kill tumor cells through a novel peroxynitrite-dependent mechanism and participate at virtually all levels of antitumor immune responses, which reinforces their interest in immunotherapy.

Houghtelin, A. B., Kopp, L. M., Pelayo-Katsanis, L., Kuo, P. H., Yeager, A. M., & Katsanis, E. (2015). Extramedullary Breast Relapse of Acute Lymphoblastic Leukemia Controlled with a Second Allogeneic/Autologous Hematopoietic Cell Transplant. Journal of adolescent and young adult oncology, 4(1), 50-3.

Relapse of acute lymphoblastic leukemia (ALL) in the breast is uncommon and often precedes systemic relapse, resulting in poor survival. We report the development of breast involvement of ALL in a 20-year-old woman 32 months after a related allogeneic peripheral blood hematopoietic cell transplantation (PBHCT) in first remission. This extramedullary relapse occurred in the continuous presence of complete donor chimerism. After systemic re-induction chemotherapy and a second PBHCT using donor cells that had been cryopreserved at first transplant, our patient has remained in second complete remission for more than 44 months.