Malignant T Cell Activation by a Bacillus Species Isolated from Cutaneous T-Cell Lymphoma Lesions

Abstract

Cutaneous T-cell lymphoma (CTCL) is a life-debilitating malignancy of lymphocytes homing to the skin. Although CTCL is thought to arise from a combination of genetic, epigenetic, and environmental factors, specific triggers are unclear. The skin is colonized by a unique microbiota and is heavily influenced by its interactions. We hypothesized that adaptive immune responses to skin commensals lead to clonal T-cell proliferation and transformation in the appropriate genetic background. We therefore collected lesional and nonlesional skin microbiota from patients with CTCL to study T cell interactions using skin T cell explants and peripheral, skin-homing CD4+ T cells. By various methods, we identified Bacillus safensis in CTCL lesions, a rare human commensal in healthy skin, and showed that it can induce malignant T cell activation and cytokine secretion. Taken together, our data suggest microbial triggers in the skin microbiota of patients with CTCL as potential instigators of tumorigenesis. Cutaneous T-cell lymphoma (CTCL) is a life-debilitating malignancy of lymphocytes homing to the skin. Although CTCL is thought to arise from a combination of genetic, epigenetic, and environmental factors, specific triggers are unclear. The skin is colonized by a unique microbiota and is heavily influenced by its interactions. We hypothesized that adaptive immune responses to skin commensals lead to clonal T-cell proliferation and transformation in the appropriate genetic background. We therefore collected lesional and nonlesional skin microbiota from patients with CTCL to study T cell interactions using skin T cell explants and peripheral, skin-homing CD4+ T cells. By various methods, we identified Bacillus safensis in CTCL lesions, a rare human commensal in healthy skin, and showed that it can induce malignant T cell activation and cytokine secretion. Taken together, our data suggest microbial triggers in the skin microbiota of patients with CTCL as potential instigators of tumorigenesis. IntroductionCutaneous T-cell lymphoma (CTCL) is a cancer of skin-homing T cells, with mycosis fungoides (MF) being the most common subtype. CTCL is conceptually similar to mucosa-homing lymphocytes in mucosa-associated lymphoid tissue lymphoma (Girardi et al., 2004Girardi M. Heald P.W. Wilson L.D. The pathogenesis of mycosis fungoides.N Engl J Med. 2004; 350: 1978-1988Google Scholar; Isaacson and Du, 2004Isaacson P.G. Du M.Q. MALT lymphoma: from morphology to molecules.Nat Rev Cancer. 2004; 4: 644-653Google Scholar). Malignant T cells are clonal and proliferate in discrete histological clusters known as Pautrier’s microabscesses within the epidermis (Robson, 2007Robson A. The pathology of cutaneous T-cell lymphoma.Oncology (Williston Park). 2007; 21: 9-12Google Scholar), presenting as scaly skin patches and plaques (Girardi et al., 2004Girardi M. Heald P.W. Wilson L.D. The pathogenesis of mycosis fungoides.N Engl J Med. 2004; 350: 1978-1988Google Scholar). With MF often presenting as a fairly indolent, however life-debilitating disease, diagnosis is challenging and requires tissue sampling, which may not routinely be performed in the early stages of the disease.Despite attempts to understand disease heterogeneity, the pathogenesis remains poorly understood. Previous studies associated CTCL with HLA class II alleles (Jackow et al., 1996Jackow C.M. McHam J.B. Friss A. Alvear J. Reveille J.R. Duvic M. HLA-DR5 and DQB1∗03 class II alleles are associated with cutaneous T-cell lymphoma.J Invest Dermatol. 1996; 107: 373-376Google Scholar), supporting the already postulated hypothesis of putative antigenic triggers being needed for T cell activation and transformation (Tan et al., 1974Tan R.S. Butterworth C.M. McLaughlin H. Malka S. Samman P.D. Mycosis fungoides--a disease of antigen persistence.Br J Dermatol. 1974; 91: 607-616Google Scholar). Interestingly, a recent study showed that an intensive regimen of intravenously given antibiotics followed by oral application ameliorated CTCL disease activity (Lindahl et al., 2019Lindahl L.M. Willerslev-Olsen A. Gjerdrum L.M.R. Nielsen P.R. Blümel E. Rittig A.H. et al.Antibiotics inhibit tumor and disease activity in cutaneous T-cell lymphoma.Blood. 2019; 134: 1072-1083Google Scholar), suggesting that microbial triggers are involved in tumorigenesis. Furthermore, an animal model of CTCL supports the involvement of the microbiome because germ-free conditions resulted in significantly milder disease, which was reversed by cohousing with specific pathogen-free housed mice (Fanok et al., 2018Fanok M.H. Sun A. Fogli L.K. Narendran V. Eckstein M. Kannan K. et al.Role of dysregulated cytokine signaling and bacterial triggers in the pathogenesis of cutaneous T-cell lymphoma.J Invest Dermatol. 2018; 138: 1116-1125Google Scholar). Despite these studies, the contribution of skin commensal antigens to human disease remains unknown. We hypothesize that an antigenic signal from the skin microbiome triggers the activation and transformation of skin-homing T cells similar to that seen in Helicobacter pylori‒promoted mucosa-associated lymphoid tissue lymphoma (Girardi et al., 2004Girardi M. Heald P.W. Wilson L.D. The pathogenesis of mycosis fungoides.N Engl J Med. 2004; 350: 1978-1988Google Scholar; Isaacson and Du, 2004Isaacson P.G. Du M.Q. MALT lymphoma: from morphology to molecules.Nat Rev Cancer. 2004; 4: 644-653Google Scholar).To investigate the role of the skin microbiome in CTCL, we performed exploratory 16S ribosomal RNA (rRNA) V1‒V3 sequencing on lesional and nonlesional skin microbiomes from seven patients with CTCL and anatomically corresponding sites in five healthy subjects (Table 1). In addition, lesional and nonlesional patient-isolated bacteria were cultured from five CTCL skin swabs. T cell isolates from lesional CTCL skin biopsies showed increased signal transducer and activator of transcription 3 (STAT3) phosphorylation compared with nonlesional T cells, which is a characteristic of malignant CTCL T cell populations (Netchiporouk et al., 2014Netchiporouk E. Litvinov I.V. Moreau L. Gilbert M. Sasseville D. Duvic M. Deregulation in STAT signaling is important for cutaneous T-cell lymphoma (CTCL) pathogenesis and cancer progression.Cell Cycle. 2014; 13: Scholar; et al., Nielsen M. et activation of in cutaneous T-cell for an of 2004; Scholar). these lesional T-cell isolates as as skin-homing T cells from patients with CTCL, we identified Bacillus safensis not patient-isolated skin bacteria as a potential of antigenic the clonal proliferation of malignant CTCL T cells. Furthermore, cytokine of the cutaneous T cells in to safensis an which was not in cells. data that skin commensal bacteria may to CTCL pathogenesis and may with as et al., E. Willerslev-Olsen A. M. L.M. S. et the malignant and CD4+ T cells in cutaneous T-cell 2019; Scholar; Willerslev-Olsen et al., A. L.M. Litvinov I.V. S. et activation and in cutaneous T-cell lymphoma.Blood. Willerslev-Olsen et al., A. L.M. C.M. et disease in cutaneous T-cell Scholar), to the antigenic and of malignant T cells that in early by for Bacillus skin skin skin skin and skin and skin skin and CTCL, cutaneous T-cell healthy mycosis not of and of and by is a and is a in a and of the CTCL skin 16S V1‒V3 of the most sites and the the subjects and sites and and of and not in microbial skin CTCL lesions, and healthy and the of S. and et al., J. S. in human skin and microbiota of healthy and Med. 4: Scholar), which may involved in CTCL pathogenesis et al., A. L.M. Litvinov I.V. S. et activation and in cutaneous T-cell lymphoma.Blood. Scholar). with a unique of Bacillus in MF skin and The 16S from of healthy subjects and subjects with et al., K. M. et of the human as triggers of in Med. 2018; Scholar; et al., et T and cells with by a common human commensal to 2019; a in the Bacillus in CTCL compared with that in healthy and and that is to the of Bacillus of these Bacillus we identified 16S V1‒V3 in five of seven patients with CTCL with to a lesional of Bacillus safensis and the safensis showed the of the identified Bacillus that are not to in and of CTCL and skin microbiomes as as isolates from lesional and nonlesional CTCL skin. as by skin of of healthy skin of from subjects with CTCL, of from healthy skin of from subjects with CTCL, of from healthy skin of from subjects with CTCL, nonlesional and lesional CTCL in was as by of The the nonlesional CTCL, and the lesional was CTCL and with the of the from the and to a sequencing of of of in healthy and MF skin by from lesional and nonlesional of patients with and nonlesional sites were and cultured in as in and of was and The an of bacterial with the identified not in not for CTCL, cutaneous T-cell healthy mycosis and of from Bacillus The 16S V1‒V3 were using to corresponding 16S V1‒V3 of a safensis from a with CTCL and a safensis 16S to in the as in safensis is in as of from a in patients with CTCL lesional and nonlesional as compared with that of in healthy CTCL, cutaneous T-cell healthy mycosis ribosomal of Bacillus The of the Bacillus identified in study and of as as the identified and skin commensals was The was using the and A. M. for and Scholar). The with the of is The of in which the associated in the are to the J. on an using the Scholar). The is to with in the as of the to the The were using the et al., K. M. S. for by using the 2004; and are in the of the of with a unique of safensis in CTCL, the Bacillus is in healthy human skin microbiomes of skin in the 16S V1‒V3 compared with in MF skin from our not the of safensis in MF skin lesional compared with skin from healthy and safensis was not identified in a of healthy skin et al., J. S. et and in the human skin 2014; Scholar), suggesting a unique role for commensal in early T cells proliferate in to bacterial transformation and proliferation of clonal T-cell populations are known to CTCL (Girardi et al., 2004Girardi M. Heald P.W. Wilson L.D. The pathogenesis of mycosis fungoides.N Engl J Med. 2004; 350: 1978-1988Google Scholar), we patient-isolated bacteria T-cell activation of malignant T cells from skin T cells from biopsies from patients with CTCL were and for T-cell as et al., A. and CD4+ T cell specific for antigens using of T Med. Scholar; et al., K. M. et of the human as triggers of in Med. 2018; Scholar; et al., et T and cells with by a common human commensal to 2019; T cells were to by with phosphorylation within the malignant CTCL T-cell (Netchiporouk et al., 2014Netchiporouk E. Litvinov I.V. Moreau L. Gilbert M. Sasseville D. Duvic M. Deregulation in STAT signaling is important for cutaneous T-cell lymphoma (CTCL) pathogenesis and cancer progression.Cell Cycle. 2014; 13: Scholar; et al., Nielsen M. et activation of in cutaneous T-cell for an of 2004; Scholar). phosphorylation was increased in lesional compared with that in nonlesional skin, supporting that malignant T cells were for in studies and (Girardi et al., 2004Girardi M. Heald P.W. Wilson L.D. The pathogenesis of mycosis fungoides.N Engl J Med. 2004; 350: 1978-1988Google of CTCL T cells from skin biopsies and for from a malignant T cells from skin that are on phosphorylation of in cutaneous lesional T cells in cutaneous nonlesional T cells of The is of CTCL, cutaneous T-cell signal transducer and activator of transcription signal transducer and activator of were using the are by T cells showed a in to safensis and not to patient-isolated skin bacteria and bacteria and to that as Furthermore, we T cells from was for safensis in skin and Bacillus by skin cutaneous antigen CD4+ et al., K. et of T cells are in et al., M. M. A. et T lymphocytes as cell in skin Dermatol. T cells in to safensis which homing of Bacillus T cells to CTCL in the of these T cells, cytokine was by a as et al., K. M. et of the human as triggers of in Med. 2018; Scholar; et al., et T and cells with by a common human commensal to 2019; and and and T cells of and data an bacterial with was in the cutaneous T cells as as in T cells and and and in patients T cell proliferation and cytokine studies using patient-isolated cutaneous T cells. responses of human malignant T cells from skin biopsies to bacteria from lesional compared with that from nonlesional to proliferation as using a from the of the cutaneous T cells for with bacteria as as and were by cytokine of and were using the are by mycosis T cell cytokine studies using patient-isolated cutaneous T cells. responses of human malignant T cells from skin biopsies to bacteria from lesional compared with that from nonlesional to proliferation as using a cytokine with cytokine from the of the cutaneous T cells for with bacteria as were by cytokine of and were using the are by mycosis T cell proliferation and cytokine studies using patient-isolated T cells. CD4+ T cells from for skin-homing and proliferation to Bacillus safensis compared with T cells. proliferation as using a from the of the cutaneous T cells for with bacteria as as and were by cytokine of and were using the are by cutaneous mycosis we skin biopsies collected microbiome from our for the of biopsies were from lesional sites and and the the of diagnosis The 16S with a et al., L. M. and of Bacillus isolates a of and 2014; and of Bacillus and Bacillus with 16S and and sequencing of Scholar; et al., H. of 16S and in the Bacillus J 2007; et al., J. H. of Bacillus and Bacillus safensis using in 2014; was to the of safensis of skin from skin disease similar to early as of the biopsies showed to the to of the lesions, supporting a role for safensis early in the disease with the and studies, it can be that the of patients with CTCL of lesional safensis that was to the of cutaneous and skin-homing T-cell proliferation and cytokine and and of skin from patients with CTCL in lesional and from The in the that was of patients the of diagnosis and The the from a of the with an T cell with the the from a of the with of mycosis fungoides and the from a of the with of by and lymphocytes with data supporting clonal T-cell of skin biopsies from patients with MF and Cutaneous lesional biopsies from patients with MF and for a 16S as as for the of and is in Cutaneous biopsies from were for is of for for CTCL, cutaneous T-cell mycosis the of CTCL, is thought to arise from malignant transformation of T cells in the of antigenic and et al., A. M. to mycosis fungoides from conditions plaques and Dermatol. Scholar; et al., 2004Girardi M. Heald P.W. Wilson L.D. The pathogenesis of mycosis fungoides.N Engl J Med. 2004; 350: 1978-1988Google Scholar). data suggest increased Bacillus in patients with CTCL compared with that in skin. We identified the rare human skin commensal safensis in patients with CTCL, within lesional skin. recent skin microbiome of patients with CTCL from which was performed by supports the of safensis and a et al., A. A. L. L. et microbiome in cutaneous T-cell lymphoma by 16S and Invest Dermatol. Scholar). The of to safensis is in Furthermore, Bacillus and which we cultured from of patients and in our study were in recent CTCL skin microbiome study from the et al., K. et T-cell lymphoma skin microbiome is by in commensal bacteria not compared with healthy Invest Dermatol. Scholar). of T-cell proliferation and cytokine a role for safensis in the pathogenesis of with early CTCL and activation of skin-homing T cells that as an of CTCL that is by by microbiota is that safensis as an antigenic which of skin-homing T cells and that and cytokine with in Pautrier’s commensals in the of et al., J. H. of the microbiota and Scholar), a of and of skin and to be in the T-cell of by safensis be of a T cell by in early stages of CTCL, T cell to immune et al., The role of cytokine signaling in the pathogenesis of cutaneous T-cell Scholar; et al., L.M. Litvinov I.V. L. et in cutaneous T-cell Scholar). studies are needed to understand safensis on malignant T-cell on T cells in the tumor is that safensis to activity by its and the of and the Bacillus 4: and Bacillus safensis and by and Scholar). may a of safensis within its In addition, studies showed that is to which to be to putative et al., E. S. et that may be for the by Bacillus Scholar). of our patients showed safensis and may to in patients with S. that its are for disease et al., E. Willerslev-Olsen A. M. L.M. S. et the malignant and CD4+ T cells in cutaneous T-cell 2019; Scholar; Willerslev-Olsen et al., A. L.M. Litvinov I.V. S. et activation and in cutaneous T-cell lymphoma.Blood. Willerslev-Olsen et al., A. L.M. C.M. et disease in cutaneous T-cell Scholar). the of S. and safensis in skin of patients with CTCL given that Bacillus can S. et al., A. M. K. et Bacillus and by Scholar). The of safensis an antigenic for the from a adaptive immune to a clonal malignant in early CTCL lesions, with S. as an immune of and CTCL pathogenesis on these is safensis as a potential antigenic can be by our in studies as in involvement of Bacillus safensis and in CTCL tumorigenesis. The hypothesized role for safensis in the pathogenesis of most common of in the a and in the skin in the safensis bacteria are as and bacteria are as Cutaneous safensis in are by cells as cells that to the in to antigens to T cells. T cells are to the skin the skin homing and The antigen in the epidermis triggers T cell proliferation and cytokine a that supports the malignant transformation of cutaneous T cells. by microbiota as by S. in the of Pautrier’s microabscesses and the of the T cell were with cutaneous CTCL, cutaneous T-cell mycosis signal transducer and activator of transcription antigens by clonal T cells that arise in unknown. recent study identified as by cells in et al., S. J. in the of Engl J Med. Scholar), the of these antigens remains to be a in which antigenic from a rare skin commensal may be a of in the skin of patients with early CTCL to sites in early mucosa-associated lymphoid tissue The of our study the of subjects the of and the of cells from skin malignant T cell which is and are needed to the of safensis Bacillus by CTCL T cells is a in of patients with Furthermore, the specific antigen antigens malignant T cell activation in our study to be studies in and are to safensis is to CTCL pathogenesis in to the of H. in early mucosa-associated lymphoid tissue can skin commensals in skin with and subjects and microbiota human were by the and in with the of was from study were in the in the in the in the disease, malignancy in the and known with CTCL and healthy to study for the of and and and nonlesional skin microbiota and healthy as and nonlesional skin microbiota were collected as et al., K. M. et of the human as triggers of in Med. 2018; Scholar). The skin were the V1‒V3 16S using the in the on 16S In using that were in were on a of skin for were were performed from the and to In addition, a skin were to environmental were in was were in for with were in the using a with for and for were on for and of was to were for and an of was to the the for the was and were by and on a from microbiota was performed as et al., K. M. et of the human as triggers of in Med. 2018; Scholar; et al., et T and cells with by a common human commensal to 2019; Scholar). The V1‒V3 of the 16S were and using the with as et al., K. M. et of the human as triggers of in Med. 2018; Scholar). of 16S sequencing was performed as et al., P.D. of a sequencing and for data on the sequencing Scholar; et al., et T and cells with by a common human commensal to 2019; with the was performed using et al., E. J.R. et and microbiome data using in 2019; with performed using the et al., from 13: for and and and were using a et al., E. J. et ribosomal RNA data and et al., A. V. et in were to and were to the of that for the of by and V1‒V3 16S were from the for human microbiome et al., D. K. et a for the healthy human Scholar). were and to as for the were using et al., A. D. K. et of using Scholar). safensis 16S as known were compared with of a safensis with were safensis an to the cultured safensis for the of Bacillus was using the and A. M. for and with an with the of The were using the et al., K. M. S. for by using the 2004; and are in the of the of The was using the and M. S. and a of The and M. The a for 4: was to the The involved with the safensis S. S. S. S. S. S. S. and S. and data were were a of in the were in et al., S. K. for and and nonlesional skin microbiota were collected using with and in of were on with the were and for and was using the for bacteria 16S was using the 16S and and by were to an of were and in for in for in proliferation D. and A. were from the of and and cell from skin lesional biopsies were from patients with CTCL skin were as by using and on followed by T cell et al., K. et for the of skin T cells from and human Invest Dermatol. In cell were with were to skin T-cell was and skin were with of skin T-cell of The skin were the and an a by the and were to were using a and were in were in a for of of skin were to and to the of using the were as in in a of as a was a of in and were using were using of cell proliferation and cytokine were from by were using the using the and CD4+ T cells using the CD4+ T cells were in human with to and to within were as cells for the T-cell CD4+ T cells from were on a was performed using to the T cells in T cells CD4+ T cells from were for in using the T cells were in using that were for 3 with cultured bacteria bacterial for to were for cytokine using a by the and as et al., K. M. et of the human as triggers of in Med. 2018; Scholar; et al., et T and cells with by a common human commensal to 2019; Scholar). proliferation was by using the the and as et al., K. M. et of the human as triggers of in Med. 2018; Scholar; et al., et T and cells with by a common human commensal to 2019; on human skin 16S in study were by a et al., L. M. and of Bacillus isolates a of and 2014; Scholar; and of Bacillus and Bacillus with 16S and and sequencing of and a et al., of 16S with for microbial Scholar). The associated with the 16S was in human skin cutaneous in Scholar). in the were with by skin biopsies were from the and were in and for We skin biopsies of patients with from a study et al., K. M. et of the human as triggers of in Med. 2018; as of was on were performed for with of was for with were and using with the were with a of data and were performed using was by and were are using for for for and for to to the and can be the the A. E. S. A. and IntroductionCutaneous T-cell lymphoma (CTCL) is a cancer of skin-homing T cells, with mycosis fungoides (MF) being the most common subtype. CTCL is conceptually similar to mucosa-homing lymphocytes in mucosa-associated lymphoid tissue lymphoma (Girardi et al., 2004Girardi M. Heald P.W. Wilson L.D. The pathogenesis of mycosis fungoides.N Engl J Med. 2004; 350: 1978-1988Google Scholar; Isaacson and Du, 2004Isaacson P.G. Du M.Q. MALT lymphoma: from morphology to molecules.Nat Rev Cancer. 2004; 4: 644-653Google Scholar). Malignant T cells are clonal and proliferate in discrete histological clusters known as Pautrier’s microabscesses within the epidermis (Robson, 2007Robson A. The pathology of cutaneous T-cell lymphoma.Oncology (Williston Park). 2007; 21: 9-12Google Scholar), presenting as scaly skin patches and plaques (Girardi et al., 2004Girardi M. Heald P.W. Wilson L.D. The pathogenesis of mycosis fungoides.N Engl J Med. 2004; 350: 1978-1988Google Scholar). With MF often presenting as a fairly indolent, however life-debilitating disease, diagnosis is challenging and requires tissue sampling, which may not routinely be performed in the early stages of the disease.Despite attempts to understand disease heterogeneity, the pathogenesis remains poorly understood. Previous studies associated CTCL with HLA class II alleles (Jackow et al., 1996Jackow C.M. McHam J.B. Friss A. Alvear J. Reveille J.R. Duvic M. HLA-DR5 and DQB1∗03 class II alleles are associated with cutaneous T-cell lymphoma.J Invest Dermatol. 1996; 107: 373-376Google Scholar), supporting the already postulated hypothesis of putative antigenic triggers being needed for T cell activation and transformation (Tan et al., 1974Tan R.S. Butterworth C.M. McLaughlin H. Malka S. Samman P.D. Mycosis fungoides--a disease of antigen persistence.Br J Dermatol. 1974; 91: 607-616Google Scholar). Interestingly, a recent study showed that an intensive regimen of intravenously given antibiotics followed by oral application ameliorated CTCL disease activity (Lindahl et al., 2019Lindahl L.M. Willerslev-Olsen A. Gjerdrum L.M.R. Nielsen P.R. Blümel E. Rittig A.H. et al.Antibiotics inhibit tumor and disease activity in cutaneous T-cell lymphoma.Blood. 2019; 134: 1072-1083Google Scholar), suggesting that microbial triggers are involved in tumorigenesis. Furthermore, an animal model of CTCL supports the involvement of the microbiome because germ-free conditions resulted in significantly milder disease, which was reversed by cohousing with specific pathogen-free housed mice (Fanok et al., 2018Fanok M.H. Sun A. Fogli L.K. Narendran V. Eckstein M. Kannan K. et al.Role of dysregulated cytokine signaling and bacterial triggers in the pathogenesis of cutaneous T-cell lymphoma.J Invest Dermatol. 2018; 138: 1116-1125Google Scholar). Despite these studies, the contribution of skin commensal antigens to human disease remains unknown. We hypothesize that an antigenic signal from the skin microbiome triggers the activation and transformation of skin-homing T cells similar to that seen in Helicobacter pylori‒promoted mucosa-associated lymphoid tissue lymphoma (Girardi et al., 2004Girardi M. Heald P.W. Wilson L.D. The pathogenesis of mycosis fungoides.N Engl J Med. 2004; 350: 1978-1988Google Scholar; Isaacson and Du, 2004Isaacson P.G. Du M.Q. MALT lymphoma: from morphology to molecules.Nat Rev Cancer. 2004; 4: 644-653Google Scholar).To investigate the role of the skin microbiome in CTCL, we performed exploratory 16S ribosomal RNA (rRNA) V1‒V3 sequencing on lesional and nonlesional skin microbiomes from seven patients with CTCL and anatomically corresponding sites in five healthy subjects (Table 1). In addition, lesional and nonlesional patient-isolated bacteria were cultured from five CTCL skin swabs. T cell isolates from lesional CTCL skin biopsies showed increased signal transducer and activator of transcription 3 (STAT3) phosphorylation compared with nonlesional T cells, which is a characteristic of malignant CTCL T cell populations (Netchiporouk et al., 2014Netchiporouk E. Litvinov I.V. Moreau L. Gilbert M. Sasseville D. Duvic M. Deregulation in STAT signaling is important for cutaneous T-cell lymphoma (CTCL) pathogenesis and cancer progression.Cell Cycle. 2014; 13: Scholar; et al., Nielsen M. et activation of in cutaneous T-cell for an of 2004; Scholar). these lesional T-cell isolates as as skin-homing T cells from patients with CTCL, we identified Bacillus safensis not patient-isolated skin bacteria as a potential of antigenic the clonal proliferation of malignant CTCL T cells. Furthermore, cytokine of the cutaneous T cells in to safensis an which was not in cells. data that skin commensal bacteria may to CTCL pathogenesis and may with as et al., E. Willerslev-Olsen A. M. L.M. S. et the malignant and CD4+ T cells in cutaneous T-cell 2019; Scholar; Willerslev-Olsen et al., A. L.M. Litvinov I.V. S. et activation and in cutaneous T-cell lymphoma.Blood. Willerslev-Olsen et al., A. L.M. C.M. et disease in cutaneous T-cell Scholar), to the antigenic and of malignant T cells that in early by for Bacillus skin skin skin skin and skin and skin skin and CTCL, cutaneous T-cell healthy mycosis not of and of and by is a and is a in a

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