Cutaneous T Cell Lymphoma Expresses Immunosuppressive CD80 (B7-1) Cell Surface Protein in a STAT5-Dependent Manner

Three cell lines of mature T cell origin derived from patients with cutaneous T cell lymphoma-leukemias (CTCL) were found to be constitutive producers of T cell growth factor (L-TCGF). These are the first reported human cell lines which constitutively produce TCGF. Biologically active TCGF could also be eluted from the surface of these cells using an acid glycine buffer under conditions that maintained cell viability, and subcellular fractionation showed that almost all the TCGF activity was associated with the plasma membrane. Over 30 other human hematopoietic cell lines derived from other disorders were unable to produce TCGF even after induction, and their acid eluates did not contain TCGF activity. L-TCGF from CTCL lines had the same biological activity as TCGF obtained from normal leukocytes (N-TCGF) in that they both supported the long-term growth of normal T cells only after the cells were previously activated by antigen or lectin. Both L-TCGF and N-TCGF increased the rate of proliferation of TCGF-independent and TCGF-dependent CTCL cell lines. The same three factor-independent cell lines that released TCGF adsorbed TCGF in a cell-concentration, time-, and temperature-dependent manner. Since the CTCL cell lines produce TCGF, adsorb TCGF, and increase their proliferative rate in response to TCGF or a related molecule, it is suggested that this endogenously produced factor plays a role in maintaining the abnormal proliferation of these cells in culture as permanently growing cell lines independent of exogenous TCGF. However, this does not mean that this is an essential aspect of neoplastic transformation. Since it is unusual to develop these cell lines in the absence of the continuous need for added TCGF, "autostimulation" may be one of the many unusual variant phenotypic properties sometimes associated with neoplastic cells that gives them a selective advantage for in vitro growth.

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Phenotypic characterization of skin-infiltrating T cells in cutaneous T- cell lymphoma: comparison with benign cutaneous T-cell infiltrates

Blood ◽

10.1182/blood.v60.2.463.463 ◽

1982 ◽

Vol 60 (2) ◽

pp. 463-473 ◽

Cited By ~ 92

Author(s):

BF Haynes ◽

LL Hensley ◽

BV Jegasothy

Keyword(s):

T Cell ◽

Cell Surface ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Skin Tests ◽

Cytotoxic T Cell ◽

Phenotypic Characterization ◽

Cell Phenotype ◽

Cutaneous T Cell Lymphoma ◽

Cell Antigen

Abstract Using a panel of monoclonal antibodies, we have studied cell surface antigens of infiltrating mononuclear cells in skin biopsies from patients with cutaneous T-cell lymphoma (CTCL) and compared them with the T-cell surface phenotype seen in benign cutaneous T-cell infiltrations (e.g., contact dermatitis, delayed hypersensitivity skin tests, granuloma annulare) and in dermal infiltrates of lymphomatoid granulomatosis patients. We found that unlike circulating CTCL (Sezary) cells, CTCL cells infiltrating skin epidermis frequently expressed the T-cell antigen 3A1. Cutaneous infiltrates in 10 patients with mycosis fungoides (MF) and 1 patient with Sezary syndrome were OKT4 (inducer T cell), OKT8 (suppressor/cytotoxic T cell); 2 patients with MF were OKT4- , OKT8; and one MF patients's skin T cell were OKT4-, OKT8+. Similar to CTCL infiltrating cells, most of the benign skin T-cell infiltrates were usually 3A1+. OKT4+, and OKT8-. Our study shows the complex nature of T-cell antigen patterns in inflammatory and malignant skin T-cell infiltrations. We demonstrated that the CTCL the skin epidermal infiltrating T-cell phenotype is not invariate, and in many cases, is similar to the phenotype of clinically benign cutaneous T-cell infiltrations.

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Phenotypic characterization of skin-infiltrating T cells in cutaneous T- cell lymphoma: comparison with benign cutaneous T-cell infiltrates

Blood ◽

10.1182/blood.v60.2.463.bloodjournal602463 ◽

1982 ◽

Vol 60 (2) ◽

pp. 463-473

Author(s):

BF Haynes ◽

LL Hensley ◽

BV Jegasothy

Keyword(s):

T Cell ◽

Cell Surface ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Skin Tests ◽

Cytotoxic T Cell ◽

Phenotypic Characterization ◽

Cell Phenotype ◽

Cutaneous T Cell Lymphoma ◽

Cell Antigen

Using a panel of monoclonal antibodies, we have studied cell surface antigens of infiltrating mononuclear cells in skin biopsies from patients with cutaneous T-cell lymphoma (CTCL) and compared them with the T-cell surface phenotype seen in benign cutaneous T-cell infiltrations (e.g., contact dermatitis, delayed hypersensitivity skin tests, granuloma annulare) and in dermal infiltrates of lymphomatoid granulomatosis patients. We found that unlike circulating CTCL (Sezary) cells, CTCL cells infiltrating skin epidermis frequently expressed the T-cell antigen 3A1. Cutaneous infiltrates in 10 patients with mycosis fungoides (MF) and 1 patient with Sezary syndrome were OKT4 (inducer T cell), OKT8 (suppressor/cytotoxic T cell); 2 patients with MF were OKT4- , OKT8; and one MF patients's skin T cell were OKT4-, OKT8+. Similar to CTCL infiltrating cells, most of the benign skin T-cell infiltrates were usually 3A1+. OKT4+, and OKT8-. Our study shows the complex nature of T-cell antigen patterns in inflammatory and malignant skin T-cell infiltrations. We demonstrated that the CTCL the skin epidermal infiltrating T-cell phenotype is not invariate, and in many cases, is similar to the phenotype of clinically benign cutaneous T-cell infiltrations.

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Targeting CD70 in cutaneous T-cell lymphoma using an antibody-drug conjugate in patient-derived xenograft models

Blood Advances ◽

10.1182/bloodadvances.2021005714 ◽

2021 ◽

Author(s):

Chi-Heng Wu ◽

Linlin Wang ◽

Chen-Yen Yang ◽

Kwun Wah Wen ◽

Brian R Hinds ◽

...

Keyword(s):

T Cell ◽

Cell Lines ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Dependent Manner ◽

Cutaneous T Cell Lymphoma ◽

Antibody Drug Conjugate ◽

Drug Conjugate ◽

T Cell Lymphomas ◽

Antibody Drug

CD70 is a member of the tumor necrosis factor (TNF) receptor superfamily. Emerging data indicate that CD70 may be a suitable target for various malignancies. We investigated the expression of CD70 in cutaneous and systemic T cell lymphomas; and conducted pre-clinical studies of SGN-CD70A, a CD70-directed antibody-drug conjugate, using patient-derived cutaneous T cell lymphoma (CTCL PDX) models. CD70 expression was examined by immunohistochemical stains in 46 diagnostic specimens of T cell lymphomas. The activities of SGN-CD70A in growth inhibition and apoptosis induction were examined in CTCL cell lines and primary CTCL tumor cells. Using previously established CTCL PDXs, we conducted a dose-finding trial, followed by a phase II-like trial, to evaluate the optimal dosing and the efficacy of SGN-CD70A in tumor-bearing PDX animals. The therapeutic efficacy of SGN-CD70A was measured by tumor-associated cell-free DNA (cfDNA) and survival of treated PDXs. We found that CD70 is highly expressed in T cell lymphomas, especially in CTCL. SGN-CD70A inhibited cell growth and induced apoptosis in CD70-expressing CTCL cell-lines and primary tumors cells. Additionally, SGN-CD70A at 100 µg/kg and 300 µg/kg prolonged survival of PDXs in a dose-dependent manner. Finally, treatment with three doses of SGN-CD70A at 300 µg/kg was superior to single dose treatment in survival prolongation (median survival: 111 days vs. 39 days, p=0.017). Most importantly, multiple-dosing of SGN-CD70A induced complete eradication of established tumors in PDXs measured by cfDNA. Our results demonstrated marked anti-tumor activity of SGN-CD70A in CTCL PDXs, providing compelling support for its clinical investigation.

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