Radiotherapy Eradicates Malignant T Cells and Is Associated with Improved Survival in Early-Stage Mycosis Fungoides

Abstract Immunotherapy is a valuable treatment for many cancer patients, and there is considerable interest in understanding the mechanisms of immune evasion to guide appropriate management. Mycosis fungoides (MF) is a malignant disorder of skin-homing CD4+ T cells, and it exhibits a highly variable clinical course during which the tumor-specific immune response may be an important determinant. An unusual feature of MF is that tumor-infiltrating lymphocytes (TILs) must attempt to control a malignant cell from within their own lineage. We obtained skin biopsies and blood from 43 patients with CD4+ MF and undertook a detailed phenotypic and functional analysis of CD4+ and CD8+ T cells. Clonotypic TCRBV staining allowed delineation of malignant and reactive CD4+ subsets. CD4+ and CD8+ TILs displayed a comparable “exhausted” phenotype that was characterized by expression of PD-1 and TIGIT but retained cytotoxic activity and production of interferon-γ and interleukin-17 in early-stage disease. In contrast, tumor cells were much more heterogeneous and were divided into 3 discrete subsets based on differential expression of HLA-DR: “cold” (DR−), “exhausted” (DR+ PD-1+), and “evasive” (DR++ PD-L1+) phenotypes. Disease progression was associated with increasing divergence of the tumor phenotype away from that of TILs and reduced functional activity within TILs. These observations reveal that the phenotype and function of TIL populations are constrained at all stages of disease, whereas the tumor evolves discrete phenotypic profiles of escape during clinical progression. The findings should help to direct appropriate immunotherapeutic interventions for individual patients.

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227 Low-dose radiation preferentially kills malignant T cells, recruits benign T cells and normalizes the immune milieu in mycosis fungoides

Journal of Investigative Dermatology ◽

10.1016/j.jid.2016.02.256 ◽

2016 ◽

Vol 136 (5) ◽

pp. S40

Author(s):

J.T. O’Malley ◽

E.L. Lowry ◽

A. Gehad ◽

J. Teague ◽

C.P. Elco ◽

...

Keyword(s):

T Cells ◽

Mycosis Fungoides ◽

Low Dose ◽

Low Dose Radiation ◽

Dose Radiation ◽

Malignant T Cells

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The epidermotropic mycosis fungoides associated α1β1 integrin (VLA-1, CD49a/CD29) is primarily a collagen IV receptor on malignant T cells

Journal of Cutaneous Pathology ◽

10.1111/j.1600-0560.1999.tb01804.x ◽

1999 ◽

Vol 26 (2) ◽

pp. 65-71 ◽

Cited By ~ 12

Author(s):

IIan Bank ◽

Edward Rapman ◽

Raisa Shapiro ◽

Ginette Schiby ◽

Iris Goldberg ◽

...

Keyword(s):

T Cells ◽

Mycosis Fungoides ◽

Collagen Iv ◽

Malignant T Cells

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FoxP3-Positive T-Regulatory Cells in Lymph Nodes with Mycosis Fungoides and Sézary Syndrome

Lymphoma ◽

10.1155/2014/597908 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Rekha Bhat ◽

Bhavna Khandpur ◽

Eric C. Vonderheid ◽

J. Steve Hou

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Lymph Nodes ◽

Mycosis Fungoides ◽

Cox Proportional Hazards Model ◽

Cell Phenotype ◽

Sézary Syndrome ◽

Sezary Syndrome ◽

Malignant T Cells

Mycosis fungoides and Sézary syndrome are indolent cutaneous T-cell lymphomas, with skin-associated peripheral lymph nodes being the most frequent extracutaneous site of involvement. Acquisition of functional properties of regulatory T-cells by malignant T-cells in advanced disease may contribute to immunosuppression. Whereas previous studies examining FoxP3 protein expression in mycosis fungoides and Sézary syndrome have focused on skin specimens, little data are available on lymph nodes from patients with these conditions. In this study we examined FoxP3+ regulatory T-cells in lymph nodes from 26 patients with mycosis fungoides and Sézary syndrome and correlated the findings with clinical data, molecular assays for T-cell clonality, and flow cytometry. Except for one case of Sézary syndrome in which malignant T-cells expressed FoxP3 protein, a significantly lower number of FoxP3-expressing cells occurred in lymph nodes that were clearly involved with lymphoma as compared to uninvolved nodes. Cox proportional hazards model showed that lymph node rating and histological evidence of transformation, but not number of FoxP3+ cells, were factors significantly associated with adverse prognosis. We speculate that modulation of FoxP3+ cells in lymph nodes involved with lymphoma might play a role in disease progression. Attainment of a regulatory T-cell phenotype by a subset of lymphoma cells might signal a poor prognosis.

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High-scatter T cells: a reliable biomarker for malignant T cells in cutaneous T-cell lymphoma

Blood ◽

10.1182/blood-2010-05-287664 ◽

2011 ◽

Vol 117 (6) ◽

pp. 1966-1976 ◽

Cited By ~ 43

Author(s):

Rachael A. Clark ◽

Jeffrey B. Shackelton ◽

Rei Watanabe ◽

Adam Calarese ◽

Kei-ichi Yamanaka ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Skin Diseases ◽

Cell Lymphoma ◽

Early Stage ◽

T Cell Lymphoma ◽

Cutaneous T Cell Lymphoma ◽

Inflammatory Skin Diseases ◽

Inflammatory Skin ◽

Malignant T Cells

Abstract In early-stage cutaneous T-cell lymphoma (CTCL), malignant T cells are confined to skin and are difficult to isolate and discriminate from benign reactive cells. We found that T cells from CTCL skin lesions contained a population of large, high-scatter, activated skin homing T cells not observed in other inflammatory skin diseases. High-scatter T (THS) cells were CD4+ in CD4+ mycosis fungoides (MF), CD8+ in CD8+ MF, and contained only clonal T cells in patients with identifiable malignant Vβ clones. THS cells were present in the blood of patients with leukemic CTCL, absent in patients without blood involvement, and contained only clonal malignant T cells. The presence of clonal THS cells correlated with skin disease in patients followed longitudinally. Clonal THS cells underwent apoptosis in patients clearing on extracorporeal photopheresis but persisted in nonresponsive patients. Benign clonal T-cell proliferations mapped to the normal low-scatter T-cell population. Thus, the malignant T cells in both MF and leukemic CTCL can be conclusively identified by a unique scatter profile. This observation will allow selective study of malignant T cells, can be used to discriminate patients with MF from patients with other inflammatory skin diseases, to detect peripheral blood involvement, and to monitor responses to therapy.

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