Résumés
Résumé
Les lymphomes T cutanés sont liés à l’accumulation, dans la peau, de lymphocytes T matures mémoires à tropisme cutané. La forme la plus fréquente est le mycosis fongoïde, le syndrome de Sézary représentant la forme disséminée avec cellules tumorales circulantes. La physiopathologie et la progression tumorale restent mal comprises, mais plusieurs découvertes récentes suggèrent le développement possible de nouvelles possibilités thérapeutiques : mise en évidence de plusieurs antigènes exprimés par les lymphocytes T tumoraux, voies de signalisation impliquées dans la résistance à l’apoptose, possibilités de stimulation de l’immunité innée. La mise en évidence récente de signatures moléculaires devrait également permettre de mettre au point de nouveaux marqueurs diagnostiques et pronostiques.
Summary
Primary cutaneous T cell lymphomas (CTCL) represent the most frequently occurring group of extra-nodal T cell lymphomas, originating from skin-homing memory T cells. Sezary syndrome (SS) is a leukemic variant of CTCL that presents with erythroderma, lymphadenopathies and presence of malignant T cells in peripheral blood. SS has an unfavourable prognosis, and is refractory to current treatments. Progress in understanding the pathogenesis and tumor progression of SS is limited. In the past few years, we have identified and reported several CTCL-associated antigens, CD158k/KIR3DL2, CD85j/ILT2, and SC5/vimentin. KIR3DL2 is the first phenotypic marker of Sezary cells that can be used for the diagnostic and follow-up of Sezary syndrome. The SC5 antibody is the only monoclonal antibody reacting with vimentin on the surface of viable Sezary cells. CTCL are characterized by a predominance of Th2 cytokines. The recent suggestion that CTCL cells could be regulatory T (Tr) cells remains controversial. Gene expression studies suggest that in the future we may develop new diagnostic and prognostic tools, and identify subsets of patients who would benefit from more appropriate treatment protocols. Future challenges are to render tumor cells sensitive to apoptosis by inhibiting specific signalling pathways such as the constitutively activated NF-KB pathway, to identify specific surface kinase receptors and to develop specific inhibitors, to develop humanized monoclonal antibodies directed against tumor specific antigens, able to kill tumor cells via complement-dependent and antibody-dependent cytotoxicity, and to stimulate innate immunity.
Parties annexes
Références
- 1. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005 ; 105 : 3768-85.
- 2. Bagot M, Echchakir H, Mami-Chouaib F, et al. Isolation of tumor-specific cytotoxic CD4+ and CD4+CD8dim+ T cell clones infiltrating a cutaneous T cell lymphoma. Blood 1998 ; 91 : 4331-41.
- 3. Dalloul A, Laroche L, Bagot M, et al. Interleukin-7 is a growth factor for Sezary lymphoma cells. J Clin Invest 1992 ; 90 : 1054-60.
- 4. Bagot M, Charue D, Boulland ML, et al. Interleukin-7 receptor expression in cutaneous T-cell lymphomas. Br J Dermatol 1996 ; 135 : 572-5.
- 5. Rich BE, Campos-Torres J, Tepper RI, et al. Cutaneous lymphoproliferation and lymphomas in interleukin 7 transgenic mice. J Exp Med 1993 ; 177 : 305-16.
- 6. Williams IR, Rawson EA, Manning L, et al. IL-7 overexpression in transgenic mouse keratinocytes causes a lymphoproliferative skin disease dominated by intermediate TCR cells : evidence for a hierarchy in IL-7 responsiveness among cutaneous T cells. J Immunol 1997 ; 159 : 3044-56.
- 7. Poszepczynska E, Bagot M, Echchakir H, et al. Functional characterization of an IL-7 dependent CD4+CD8alpha+ Th3-type malignant cell line derived from a patient with a cutaneous T-cell lymphoma. Blood 2000 ; 96 : 1056-63.
- 8. Michel L, Dupuy A, Jean-Louis F, et al. Arsenic trioxide induces apoptosis of cutaneous T cell lymphoma cells : evidence for a partially caspase-independent pathway and potentiation by ascorbic acid (vitamin C). J Invest Dermatol 2003 ; 121 : 881-93.
- 9. Edelman J, Meyerson HJ. Diminished CD3 expression is useful for detecting and enumerating Sezary cells. Am J Clin Pathol 2000 ; 114 : 467-77.
- 10. Laetsch B, Haffner AC, et al. CD4+/CD7- T cell frequency and polymerase chain reaction-based clonality assay correlate with stage in cutaneous T cell lymphomas. J Invest Dermatol 2000 ; 114 : 107-11.
- 11. Bernengo MG, Novelli M, Quaglino P, et al. The relevance of the CD4+ CD26- subset in the identification of circulating Sezary cells. Br J Dermatol 2001 ; 144 : 125-35.
- 12. Dereure O, Portales P, Clot J, Guilhou JJ. Decreased expression of Fas (APO-1/CD95) on peripheral blood CD4+ T lymphocytes in cutaneous T-cell lymphomas. Br J Dermatol 2000 ; 143 : 1205-10.
- 13. Pende D, Biassoni R, Cantoni C, et al. The natural killer cell receptor specific for HLA-A allotypes : a novel member of the p58/p70 family of inhibitory receptors that is characterized by three immunoglobulin-like domains and is expressed as a 140-kD disulphide-linked dimer. J Exp Med 1996 ; 184 : 505-18.
- 14. Moretta A, Biassoni R, Bottino C, et al. Major histocompatibility complex class I-specific receptors on human natural killer and T lymphocytes. Immunol Rev 1997 ; 155 : 105-17.
- 15. Bagot M, Moretta A, Sivori S, et al. CD4+ cutaneous T cell lymphoma cells express the p140/killer cell immunoglobulin-like receptor. Blood 2001 ; 97 : 1388-91.
- 16. Wechsler J, Bagot M, Nikolova M, et al. Killer cell immunoglobulin-like receptor expression delineates in situ Sezary syndrome lymphocytes. J Pathol 2003 ; 199 : 77-83.
- 17. Poszepczynska-Guigné E, Schiavon V, D’Incan M, et al. CD158k/KIR3DL2 is a new phenotypic marker of Sezary cells : relevance for the diagnostic and follow-up of Sezary syndrome. J Invest Dermatol 2004 ; 122 : 820-3.
- 18. Nikolova M, Musette P, Bagot M, et al. Engagement of ILT2/CD85j in Sézary syndrome cells inhibits their CD3/TCR signaling. Blood 2002 ; 100 : 1019-25.
- 19. Bagot M, Nikolova M, Schirm-Chabanette F, et al. Crosstalk between tumor T lymphocytes and reactive T lymphocytes in cutaneous T cell lymphomas. Ann NY Acad Sci 2001 ; 941 : 31-8.
- 20. Nikolova M, Tawab A, Marie-Cardine A, et al. Increased expression of a novel early activation surface membrane receptor in cutaneous T cell lymphoma cells. J Invest Dermatol 2001 ; 116 : 731-8.
- 21. Echchakir H, Bagot M, Dorothee G, et al. Cutaneous T cell lymphoma reactive CD4+ cytotoxic T lymphocyte clones display a Th1 cytokine profile and use a fas-independent pathway for specific tumor cell lysis. J Invest Dermatol 2000 ; 115 : 74-80.
- 22. Berger CL, Tigelaar R, Cohen J, et al. Cutaneous T-cell lymphoma : malignant proliferation of T regulatory cells. Blood 2005 ; 105 : 1640-7.
- 23. Yawalkar N, Ferenczi K, Jones DA, et al. Profound loss of T cell receptor repertoire complexity in cutaneous T-cell lymphoma. Blood 2003 ; 102 :4059-66.
- 24. Muche M, Karenko L, Gellrich S, et al. Cellular coincidence of clonal T cell receptor rearrangements and complex clonal chromosomal aberrations. A hallmark of malignancy in cutaneous T cell lymphoma. J Invest Dermatol 2004 ; 122 : 574-8.
- 25. Mao X, Orchard G, Lillington DM, et al. BCL2 and JUNB abnormalities in primary cutaneous lymphomas. Br J Dermatol 2004 ; 151 : 546-56.
- 26. Van Doorn R, Dijkman R, Vermeer MH, et al. Aberrant expression of the tyrosine kinase receptor EphA4 and the transcription factor twist in Sezary syndrome identified by gene expression analysis. Cancer Res 2004 ; 64 : 5578-86.
- 27. Su MW, Dorocicz I, Dragowska WH, et al. Aberrant expression of T-plastin in Sezary cells. Cancer Res 2003 ; 63 : 7122-7.
- 28. Tracey L, Villuendas R, Ortiz P, et al. Identification of genes involved in resistance to interferon-alpha in cutaneous T-cell lymphoma. Am J Pathol 2002 ; 161 : 1825-37.
- 29. Kari L, Loboda A, Nebozhyn M, et al. Classification and prediction of survival in patients with the leukemic phase of cutaneous T cell lymphoma. J Exp Med 2003 ; 197 : 1477-88.
- 30. Tracey L, Villuendas R, Dotor AM, et al. Mycosis fungoides shows concurrent deregulation of multiple genes involved in the TNF signaling pathway : an expression profile study. Blood 2003 ; 102 : 1042-50.