I focus my research on the mechanisms of immunoediting and immune escape of malignant and pathogen-infected cells

Induction of apoptosis in virus-infected or tumor cells by cytotoxic T cells (CTLs) is mediated by at least two mechanisms: granule-mediated exocytosis of cytolytic molecules and triggering of death receptors expressed on the surface of target cells. Secreted and surface associated molecules expressed by CTLs and involved in triggering death of target cells are referred to as effector molecules.

In the course of tumor development and progression, immunological effector molecules can mediate multiple and sometimes opposing effects such as (i) induction of tumor cell death; (ii) enhancement of tumor immunogeneicity or/and antigeneicity; (iii) immunoediting of cancer leading to tumor immune escape, and (iiii) promotion of tumor growth. My current research interests include analysis of various effects exerted by the immune system on human tumor cells. In our work, we are aiming at:

(I) Identification of signals modulating the MHC class I antigen presentation in tumor and pathogen infected cells;

(II) Description of mechanism(s) leading to the reduced susceptibility of tumors to cytotoxic T lymphocyte (CTL)-mediated killing induced via granule exocytosis and death receptors;

(III) Dissection of non-apoptotic signaling pathways transduced via surface death receptors in the regulation of tumor growth.

Topics of current research in tumor immunology

1. Mechanisms of target cell resistance to perforin/granzyme mediated killing

2. Caspase-independent control of tumor cells by bystander immune activation

3. Autocrine TNF signaling as a target in cancer therapy

Topics of current research in infectious immunity

1. Immune modulation of host cells at the early stages of malaria infection.

2. Role of malaria infection in the pathogenesis of B cell malignancies.

For detailed description of current projects visit my home page

Tumor immunology, Infectious immunity, Antigen presentation, Immunogeneicity, cytotoxic T lymphocytes (CTLs), Immunoediting, Immune escape, Autocrine TNF signaling, Bystander immune activation, Immune escape of malaria parasite, Burkitt’s lymphoma, Uveal melanoma, Neuroblastoma

1. Hallermalm K, Seki K, De Geer A, Motyka B, Bleackley CR, Jager M, Froelich, Kiessling R, Levitsky V and Jelena Levitskaya. Modulation of the tumor cell phenotype by interferon-gamma results in resistance of uveal melanoma cells to granule-mediated lysis by cytotoxic lymphocytes. J Immunology. 2008. Mar15;180(6):3766-74

2. Carlson LM, De Geer A, Kogner P. and Levitskaya Jelena. Differentiation induced by physiological and pharmacological stimuli leads to increased antigenicity of human neuroblastoma cells. Cell Research. 2008 Mar;18(3):398-411.

3. De Geer A., Carlson LM, Kogner P. and Levitskaya Jelena. Soluble factors released by activated cytotoxic T lymphocytes interfere with death receptor pathways in neuroblastoma. Cancer Immunol Immunother. 2007. Oct 26.

4. Vertuani S, Dubrovska E, Levitsky V, Jager MJ, Kiessling R and Jelena Levitskaya. Retinoic acid elicits cytostatic, cytotoxic and immunomodulatory effects on uveal melanoma cells. Cancer Immunol Immunother. 2007, Feb; 56(2):193-204.

5. Anna De Geer, Rolf Kiessling, Victor Levitsky and Jelena Levitskaya. Cytotoxic T lymphocytes Induce Caspase-Dependent and -Independent Cell Death in Neuroblastomas in a MHC-Non-Restricted Fashion. J. Immunology. 2006 Dec 1;177(11):7540-50

6. Guerreiro-Cacais A. O., Uzunel M, Levitskaya Jelena and Levitsky V. Inhibition of the heavy chain and {beta}2-microglobulin synthesis as a mechanism of MHC class I downregulation during Epstein-Barr virus replication. J Virology. 2006 Nov 15;

7. K. Hallermalm, A. De Geer, R. Kiessling, V. Levitsky and Jelena Levitskaya. Autocrine secretion of Fas ligand shields tumor cells from Fas-mediated killing by cytotoxic lymphocytes. Cancer Research. 2004 Sep 15;64(18):6775-82.

8. S. Vertuani, A. De Geer, V. Levitsky, P. Kogner, R. Kiessling and Jelena Levitskaya. Retinoids act as multi-step modulators of the major histocompatibility class I presentation pathway and sensitize neuroblastomas to cytotoxic lymphocytes. Cancer Research. 2003.Nov 15;63(22):8006-13.

9. K.-J. Malmberg, V. Levitsky, C. Teixeira de Matos, H. Norell, K. Schedvins, A. Moretta, K. Söderström, Jelena Levitskaya, Rolf Kiessling. IFN-g protects short-term ovarian carcinoma cell lines from cytotoxic T lymphocyte lysis via a CD94/NKG2A dependent mechanism. The Journal of Clinical Investigations, 2002 Nov; 110(10):1515-23.

10. Hallermalm, K., Seki, K., Wei, C., Castelli, C., Rivoltini, L., Kiessling, R., and Jelena Levitskaya. Tumor nesrosis factor (TNF)alfa induces coordinated changes in the major histocompatibility complex (MHC) class I presentation pathway resulting in increased stability of class I complexes at the cell surface. 2001. Blood. Vol.98. 1108-1114.

11. Levitskaya J., Sharipo A., Leonchiks A., Ciechanover A., Masucci M. Inhibition of ubiquiti-proteasome-dependent protein degradation by the Gly-Ala repeat domain of the Epstein-Barr virus nuclear antigen (EBNA)1. Proc. Nat. Acad. Sci. 1997. Vol. 94, 12616-12612.

12. Levitsky V., Zhang Q-J., Levitskaya J., Masucci M.G. The life-span of MHC:peptide complexes influences the efficiency of presentation and immunogenicity of two class I-restricred epitopes in the Epstein-Barr virus nuclear antigen-4. 1996. J. Exp. Medicine. Vol.183, 1-12

13. Levitskaya J., Coram M, Levitsky V, Imreh S, Steigwarld-Mullen P, Masucci M. Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen (EBNA)1. Nature. 1995.375, 685-688.