Interferon resistance of cutaneous T-cell lymphoma–derived clonal T-helper 2 cells allows selective viral replication

Abstract

IntroductionPrimary cutaneous lymphomas are the second most common group of extranodal non-Hodgkin lymphomas after primary gastrointestinal lymphomas. 1 They have highly characteristic clinical features and are considered prototype malignancies because they can be recognized clinically very early. In addition, because of their locations, they are well accessible for the study of immune and molecular biology. Most cutaneous lymphomas are low-grade T-cell lymphomas such as mycosis fungoides and Sézary syndrome (SS). 2 These neoplasms are not curable, even using aggressive chemotherapy and radiotherapy. 3 The malignant lymphocytes mostly express the T-cell markers CD2, CD3, CD4, and CD5. Often they lack CD7, and they display T-helper 2 (Th2) cytokines such as IL-5 and IL-10 and express the IFN-␥ receptor chain 2 (IFN␥R2). 4 IFN-␣, alone or in combination with retinoids or psoralen plus ultraviolet A irradiation, is helpful, especially in early disease. 5 Interferons are known for their pleiotropic effects. Besides the up-regulation of major histocompatibility complex molecules and the inhibition of cell proliferation and tumor growth, IFN can induce resistance to viral replication in all cells. 6 Interferons exert their effects by inducing overlapping sets of effector proteins through specific cell surface receptors (IFN␣R and IFN␥R). In this context, a cross-talk between IFN-␥ and IFN-␣/␤ signaling components has been reported recently. 7 It has been shown that the IFN␣R1 chain favors the association of the IFN␥R1 and the IFN␥R2 chains.Because of the beneficial clinical impact of IFN-␣ and the inhibitory potential of IFN-␥ on benign human and murine Th2 lymphocytes, 8 we studied the effects of IFNs on CTCL-derived tumor cells purified by FACS-sorting from the peripheral blood of 4 patients with SS. 4 This subtype of cutaneous T-cell lymphoma is characterized by an accumulation of malignant T-lymphocytes in skin and peripheral blood. 2 Furthermore, we evaluated the susceptibility of these SS cells to viral infections with vesicular stomatitis virus (VSV). Patients and methods PatientsSS was diagnosed using standard clinical criteria (erythroderma, lymphadenopathy), histologic criteria (subepidermal lymphoid infiltrate showing strong epidermotropism and expressing a T-helper cell phenotype), hematologic criteria (more than 1000 SS cells/mL), and an elevated CD4-CD8 ratio. 9-12 All patients were seronegative for human T-cell lymphocytic virus-I antibodies by enzyme-linked immunosorbent assay. Of the 4 patients whose T-cell clones were identified and investigated, 2 were in stage III (T 4 N 1 M 0) and 2 were in stage IVa (T 4 N 3 M 0 ) disease. 13 They did not receive any systemic therapy in the last 4 weeks before blood was taken. However, topical steroids had to be applied to control itching.Molecular biology studies for the T-cell receptor ␥ chain, 14 Southern blot analysis, or both documented the presence of a dominant T-cell clone in the peripheral blood of all patients. In all patients, a dominant CD4 ϩ V␤ ϩ (do...

IGF-1 down-regulates IFN-γR2 chain surface expression and desensitizes IFN-γ/STAT-1 signaling in human T lymphocytes

“…45 The resistance of malignant T cells to IFN-␥-induced apoptosis may be a consequence of the down-regulation of IFN-␥R2. 13,46 Our data suggest that by reinstating IFN-␥-induced STAT-1 activation and apoptosis, IGF-1R blockade may offer a way of overcoming the resistance of malignant T cells to IFN-␥. In vivo experiments are in progress to ascertain the effect of combined administration of anti-IGF-1R mAb and IFN-␥ on the growth of malignant T cells in severe combined immunodeficiency (SCID) mice.…”

Type I IFN innate immune response to adenovirus-mediated IFN-γ gene transfer contributes to the regression of cutaneous lymphomas

“…Tumor cells in CTCL have been shown to have various defects in type I/II IFN signaling and subsequent induction of ISGs (15)(16)(17)(18). Downregulation of STAT1 expression is one of the most frequently described defects accounting for resistance to IFN-α and IFN-γ stimulation (15,16). Our current data are in line with these observations and show lack of STAT1 and STAT2 induction in nonresponder CTCL patients.…”

“…Tumor cells in CTCL have been described to have defects at different levels in type I/II IFN signaling (including altered ISG expression), a phenomenon termed IFN resistance (15)(16)(17)(18). Given that all of the patients who did not mount an OR had CTCL, we investigated the expression of an additional panel of genes involved in type I/II IFN signaling (IFN-α/γ, IRF7, STAT1/2, JAK1/2, IFNAR1/2, IFNGR1/2) in baseline and posttreatment 3 skin samples by real-time PCR.…”

Paucity of FOXP3+ cells in skin and peripheral blood distinguishes Sézary syndrome from other cutaneous T-cell lymphomas

“…2 In contrast, the more aggressive Sézary syndrome is defined by erythroderma, generalized lymphadenopathy and circulating tumor cells in the peripheral blood (41000 cells/mm 3 ). 3 Cutaneous T-cell lymphomas represent monoclonal proliferations of CD4 þ T cells that produce Th2 cytokines 4 and show resistance to interferon-g. 5 One study examined the CD25 expression of CTCL tumor cells in 17 CTCL patients showing a median of 20% CD25 þ tumor cells in skin samples, which was comparable to skin specimens from patients with chronic dermatitis (5-20%). 6 Unfortunately, detailed results on CD25 expression in MF and Sézary patients were not supplied, as all patients were summarized in the CTCL group.…”