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Plasmacytoid DCs and cancer: a new role for an enigmatic cell
Update
TRENDS in Immunology
Vol.25 No.8 August 2004
| Letter
Plasmacytoid DCs and cancer: a new role for an enigmatic cell Mohamad Mohty1,2,3, Daniel Olive1,2,4 and Be´atrice Gaugler1,2 1
Laboratoire d’Immunologie des Tumeurs, Institut Paoli-Calmettes, 232 Bd. Ste Marguerite, 13273 Marseille, Cedex 09, France INSERM UMR 599, 13273 Marseille, Cedex 09, France 3 Unite´ de Transplantation et de The´rapie Cellulaire (UTTC), De´partement d’He´matologie, Institut Paoli-Calmettes, 232 Bd. Ste Marguerite, 13273 Marseille, France 4 Universite´ de la Me´diterrane´e, Marseille, France 2
In the May issue of Trends in Immunology, Coventry and Heinzel reviewed the role of CD1aþ infiltrating dendritic cells (DCs) in human cancers. Several lines of evidence suggest a possible association between CD1a expression and the capacity for presentation of some tumourassociated antigens. CD1aþ DC dysfunction might represent an important mechanism contributing to the immunosuppression observed within malignant lesions [1]. For a long time, the crucial role of DCs in cancer was underestimated. The potency of DCs for induction of immune responses can be affected by a number of aspects related to their development, maturation stage and state of activation (Box 1). Nevertheless, CD1aþ infiltrating DC dysfunction might represent only one aspect of the complex interactions between DCs and malignant tumour cells. In addition to CD1aþ DCs, a rapidly growing body of data established that other DC subsets, especially plasmacytoid DCs (PDCs), might represent another favoured target for cancer evasion from immune control. Human DC precursors are commonly divided into at least two phenotypically and functionally distinct subsets: the so-called myeloid CD1aþCD11cþ DCs and CD1a2CD11c2CD123þ PDCs. CD1aþ DCs can produce interleukin-12 (IL-12) in response to bacterial extracts and/or inflammatory cytokines, whereas PDCs differentiate in the presence of IL-3 into a distinct DC population that lacks most of the typical myeloid markers, as well as the ability to produce IL-12. Upon viral infection, PDCs, but not the myeloid CD1aþ DC precursors, produce high amounts of type I interferons (IFNs) [2] that act in an autocrine manner to promote PDC differentiation into efficient antigen-presenting cells (APCs). More than fifteen years ago, clusters of PDCs were observed in the metastatic lymph nodes draining breast carcinomas [3]. PDCs are also found to contribute to the cellular reaction in Hodgkin’s disease [4]. In primary melanomas, an increase in DCs is found in the epidermis and the peritumoural area. Interestingly, intraepidermal DCs are mostly CD1aþ Langerinþ Langerhans cells. Peritumoural DCs include a large population of DC-SIGN (DC-specific intercellular adhesion molecule-grabbing non-integrin)þmannose receptorþCD1a2 DCs, a small subset of CD1aþ DCs and, remarkably, PDCs. The PDCs, Corresponding author: Mohamad Mohty ([email protected]). Available online 28 May 2004 www.sciencedirect.com
probably recruited by stromal cell-derived factor-1 (SDF-1) secreted by melanoma cells, produce type I IFN, however, the expression of the IFN-a-inducible protein MxA is very limited. All DC subsets are predominantly immature. The peritumoural area also contains a minor subset of mature CD1aþ DCs. However, the small amount of local IL-12p40 mRNA and the naı¨ve phenotype of peritumoural T lymphocytes are consistent with poor T-cell stimulation [5]. The role of PDCs was also investigated in human ovarian epithelial tumour cells. High levels of SDF-1 secreted by malignant cells induce PDC chemotaxis while upregulating VLA-5 (very late antigen-5) expression. Tumour PDCs induce significant T-cell IL-10, unrelated to PDC differentiation or activation state, and this contributes to poor T-cell activation. In this study, CD1aþ DCs were not detected [6]. PDCs also infiltrate tumour tissue of patients with head and neck squamous cell carcinoma (HNSCC). HNSCC diminishes the ability of PDCs to produce IFN-a. Tumour-induced downregulation of Tolllike receptor 9 (TLR9) was identified as one mechanism probably contributing to impaired PDC function within the tumour environment [7]. Box 1. Cancer cell interference with dendritic cells (DCs) A substantial body of evidence depicted several ‘check-points’, at which malignant cells could interfere with DC function. Schematically, tumour –DC interactions can take place at different levels: (i) DC development and activation, (ii) antigen cross-presentation, and (iii) DC –T-cell interaction and co-stimulation. Soluble factors or cytokines from tumour cells can impair DC development and maturation. Such effects are illustrated in different haematological and non-haematological malignancies. For instance, macrophagecolony-stimulating factor (M-CSF), interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF), secreted by multiple myeloma cells and numerous solid tumours can promote monocytes, macrophages and poor antigen-presenting cells, to the detriment of DCs. Early tumour apoptotic cells can inhibit DC maturation through IL-10 or transforming growth factor-b (TGF-b). As a corollary, inhibition of DC maturation can result in poor presentation of tumour-associated antigens, related to modulation of TAP (transporter associated with antigen processing) activity or availability of lysosomal proteases. Negative regulation of stimulatory cytokines [IL-12, interferon-a (IFN-a), IFN-g] or co-stimulatory pathways (CD40 – CD40L, B7 molecules) would alter DC –T-cell interactions. Ultimately, in addition to the capacity of some tumours to downregulate MHC class I molecules or decrease heat-shock proteins, the conjunction of these phenomenons would result in a defective cytotoxic T-lymphocyte priming, T helper anergy and tolerance.
Update
398
TRENDS in Immunology
Vol.25 No.8 August 2004
We have extensively analyzed the status and function of circulating DCs in patients with haematological malignancies. There is a significant reduction in PDCs in patients with chronic myeloid leukaemia [8], which is in sharp contrast to patients suffering from acute myeloid leukaemia (AML). In AML, leukemic PDCs, but not leukemic myeloid DCs, have an impaired capacity for maturation, a decreased allostimulatory activity and are altered in their ability to secrete IFN-a [9]. Given the capacity of PDCs to efficiently expand specific cytotoxic T lymphocytes (CTLs) and Th1 CD4þ T cells [10], these results pinpoint the major role of PDCs in the adaptive immune response, which in a particular microenvironment or in the absence of appropriate stimulation are likely to promote regulatory CD8þ T cells, contributing to an impaired T cell-mediated antitumour immune response. As outlined by Coventry and Heinzel [1], several tumour-derived products, such as gangliosides, prostanoids or vascular endothelial growth factor (VEGF), might have a major role in the function of defective CD1aþ DCs. Regardless of CD1a expression, IL-10 secretion by tumour cells or the tumour microenvironment probably represents another major culprit in converting DCs into tolerogenic APCs. DCs exposed to IL-10 have strongly reduced stimulatory capacities, while inducing a state of alloantigen-specific anergy in both primed and naı¨ve CD45RAþ CD8þ T cells. In contrast to optimally stimulated CD8þ T cells, anergic tyrosinase-specific CD8þ T cells, after co-culture with peptide-pulsed IL-10-treated DCs, fail to lyse tyrosinase-expressing melanoma cells [11]. IL-10 is also likely to represent a key factor in the maintenance of peripheral tolerance. IL-10 can induce the differentiation of T regulatory cells that can mediate antigen-specific tolerance in experimental models of autoimmunity and transplantation [12]. Growth of tumours in patients itself implies host unresponsiveness, however, the question of whether this is the result of true anergy to tumour antigens or simply a failure to recognize these antigens is largely unknown. A fine understanding of the subtle mechanisms of DC defects
that result in a lack of efficient immune responses would enable deciphering some of the mechanisms of tumour immune escape [13], paving the way to new DC-based therapeutic approaches or pharmacological manipulation of DC-mediated immunity. References 1 Coventry, B. and Heinzel, S. (2004) CD1a in human cancers: a new role for an old molecule. Trends Immunol. 25, 242 – 248 2 Cella, M. et al. (1999) Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat. Med. 5, 919 – 923 3 Horny, H.P. et al. (1987) Immunocytology of plasmacytoid T cells: marker analysis indicates a unique phenotype of this enigmatic cell. Hum. Pathol. 18, 28– 32 4 Facchetti, F. et al. (1989) Plasmacytoid monocytes (so-called plasmacytoid T cells) in Hodgkin’s disease. J. Pathol. 158, 57 – 65 5 Vermi, W. et al. (2003) Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas. J. Pathol. 200, 255– 268 6 Zou, W. et al. (2001) Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat. Med. 7, 1339 – 1346 7 Hartmann, E. et al. (2003) Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer. Cancer Res. 63, 6478 – 6487 8 Mohty, M. et al. (2002) Low blood dendritic cells in chronic myeloid leukaemia patients correlates with loss of CD34þ/CD382 primitive haematopoietic progenitors. Br. J. Haematol. 119, 115 – 118 9 Mohty, M. et al. (2001) Circulating blood dendritic cells from myeloid leukemia patients display quantitative and cytogenetic abnormalities as well as functional impairment. Blood 98, 3750 – 3756 10 Fonteneau, J.F. et al. (2003) Activation of influenza virus-specific CD4þ and CD8þ T cells: a new role for plasmacytoid dendritic cells in adaptive immunity. Blood 101, 3520– 3526 11 Steinbrink, K. et al. (1999) Interleukin-10-treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8þ T cells resulting in a failure to lyse tumor cells. Blood 93, 1634– 1642 12 Roncarolo, M.G. et al. (2001) Differentiation of T regulatory cells by immature dendritic cells. J. Exp. Med. 193, F5 – F9 13 Mohty, M. et al. (2002) Leukemic dendritic cells: potential for therapy and insights towards immune escape by leukemic blasts. Leukemia 16, 2197– 2204 1471-4906/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.it.2004.05.005
| Letter Response
Reply to Mohty et al.: Dysfunctional DC subgroups in human cancers Brendon J. Coventry and Susanne Heinzel Adelaide Melanoma Unit, Breast-Endocrine and Surgical Oncology Unit; and Tumour Immunology Laboratory, Department of Surgery, University of Adelaide, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia
Recent data indicate that dendritic-cell (DC) subgroups are dysfunctional in human cancers. The mechanisms for this are currently unclear. Mohty et al. raise a number of interesting issues in their accompanying letter related to Corresponding author: Brendon J. Coventry ([email protected]). Available online 17 June 2004 www.sciencedirect.com
the types and possible functions of different sub-groups of DCs in human cancers [1]. These comments are timely and highlight the possible role of DCs in the activation or inhibition of the antitumour immune response. ‘Plasmacytoid’ DCs (PDCs) appear to have an important part in the regulation of antitumour immune responses. PDCs can expand antigen-specific T cells [2], induce
TRENDS in Immunology
Vol.25 No.8 August 2004
| Letter
Plasmacytoid DCs and cancer: a new role for an enigmatic cell Mohamad Mohty1,2,3, Daniel Olive1,2,4 and Be´atrice Gaugler1,2 1
Laboratoire d’Immunologie des Tumeurs, Institut Paoli-Calmettes, 232 Bd. Ste Marguerite, 13273 Marseille, Cedex 09, France INSERM UMR 599, 13273 Marseille, Cedex 09, France 3 Unite´ de Transplantation et de The´rapie Cellulaire (UTTC), De´partement d’He´matologie, Institut Paoli-Calmettes, 232 Bd. Ste Marguerite, 13273 Marseille, France 4 Universite´ de la Me´diterrane´e, Marseille, France 2
In the May issue of Trends in Immunology, Coventry and Heinzel reviewed the role of CD1aþ infiltrating dendritic cells (DCs) in human cancers. Several lines of evidence suggest a possible association between CD1a expression and the capacity for presentation of some tumourassociated antigens. CD1aþ DC dysfunction might represent an important mechanism contributing to the immunosuppression observed within malignant lesions [1]. For a long time, the crucial role of DCs in cancer was underestimated. The potency of DCs for induction of immune responses can be affected by a number of aspects related to their development, maturation stage and state of activation (Box 1). Nevertheless, CD1aþ infiltrating DC dysfunction might represent only one aspect of the complex interactions between DCs and malignant tumour cells. In addition to CD1aþ DCs, a rapidly growing body of data established that other DC subsets, especially plasmacytoid DCs (PDCs), might represent another favoured target for cancer evasion from immune control. Human DC precursors are commonly divided into at least two phenotypically and functionally distinct subsets: the so-called myeloid CD1aþCD11cþ DCs and CD1a2CD11c2CD123þ PDCs. CD1aþ DCs can produce interleukin-12 (IL-12) in response to bacterial extracts and/or inflammatory cytokines, whereas PDCs differentiate in the presence of IL-3 into a distinct DC population that lacks most of the typical myeloid markers, as well as the ability to produce IL-12. Upon viral infection, PDCs, but not the myeloid CD1aþ DC precursors, produce high amounts of type I interferons (IFNs) [2] that act in an autocrine manner to promote PDC differentiation into efficient antigen-presenting cells (APCs). More than fifteen years ago, clusters of PDCs were observed in the metastatic lymph nodes draining breast carcinomas [3]. PDCs are also found to contribute to the cellular reaction in Hodgkin’s disease [4]. In primary melanomas, an increase in DCs is found in the epidermis and the peritumoural area. Interestingly, intraepidermal DCs are mostly CD1aþ Langerinþ Langerhans cells. Peritumoural DCs include a large population of DC-SIGN (DC-specific intercellular adhesion molecule-grabbing non-integrin)þmannose receptorþCD1a2 DCs, a small subset of CD1aþ DCs and, remarkably, PDCs. The PDCs, Corresponding author: Mohamad Mohty ([email protected]). Available online 28 May 2004 www.sciencedirect.com
probably recruited by stromal cell-derived factor-1 (SDF-1) secreted by melanoma cells, produce type I IFN, however, the expression of the IFN-a-inducible protein MxA is very limited. All DC subsets are predominantly immature. The peritumoural area also contains a minor subset of mature CD1aþ DCs. However, the small amount of local IL-12p40 mRNA and the naı¨ve phenotype of peritumoural T lymphocytes are consistent with poor T-cell stimulation [5]. The role of PDCs was also investigated in human ovarian epithelial tumour cells. High levels of SDF-1 secreted by malignant cells induce PDC chemotaxis while upregulating VLA-5 (very late antigen-5) expression. Tumour PDCs induce significant T-cell IL-10, unrelated to PDC differentiation or activation state, and this contributes to poor T-cell activation. In this study, CD1aþ DCs were not detected [6]. PDCs also infiltrate tumour tissue of patients with head and neck squamous cell carcinoma (HNSCC). HNSCC diminishes the ability of PDCs to produce IFN-a. Tumour-induced downregulation of Tolllike receptor 9 (TLR9) was identified as one mechanism probably contributing to impaired PDC function within the tumour environment [7]. Box 1. Cancer cell interference with dendritic cells (DCs) A substantial body of evidence depicted several ‘check-points’, at which malignant cells could interfere with DC function. Schematically, tumour –DC interactions can take place at different levels: (i) DC development and activation, (ii) antigen cross-presentation, and (iii) DC –T-cell interaction and co-stimulation. Soluble factors or cytokines from tumour cells can impair DC development and maturation. Such effects are illustrated in different haematological and non-haematological malignancies. For instance, macrophagecolony-stimulating factor (M-CSF), interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF), secreted by multiple myeloma cells and numerous solid tumours can promote monocytes, macrophages and poor antigen-presenting cells, to the detriment of DCs. Early tumour apoptotic cells can inhibit DC maturation through IL-10 or transforming growth factor-b (TGF-b). As a corollary, inhibition of DC maturation can result in poor presentation of tumour-associated antigens, related to modulation of TAP (transporter associated with antigen processing) activity or availability of lysosomal proteases. Negative regulation of stimulatory cytokines [IL-12, interferon-a (IFN-a), IFN-g] or co-stimulatory pathways (CD40 – CD40L, B7 molecules) would alter DC –T-cell interactions. Ultimately, in addition to the capacity of some tumours to downregulate MHC class I molecules or decrease heat-shock proteins, the conjunction of these phenomenons would result in a defective cytotoxic T-lymphocyte priming, T helper anergy and tolerance.
Update
398
TRENDS in Immunology
Vol.25 No.8 August 2004
We have extensively analyzed the status and function of circulating DCs in patients with haematological malignancies. There is a significant reduction in PDCs in patients with chronic myeloid leukaemia [8], which is in sharp contrast to patients suffering from acute myeloid leukaemia (AML). In AML, leukemic PDCs, but not leukemic myeloid DCs, have an impaired capacity for maturation, a decreased allostimulatory activity and are altered in their ability to secrete IFN-a [9]. Given the capacity of PDCs to efficiently expand specific cytotoxic T lymphocytes (CTLs) and Th1 CD4þ T cells [10], these results pinpoint the major role of PDCs in the adaptive immune response, which in a particular microenvironment or in the absence of appropriate stimulation are likely to promote regulatory CD8þ T cells, contributing to an impaired T cell-mediated antitumour immune response. As outlined by Coventry and Heinzel [1], several tumour-derived products, such as gangliosides, prostanoids or vascular endothelial growth factor (VEGF), might have a major role in the function of defective CD1aþ DCs. Regardless of CD1a expression, IL-10 secretion by tumour cells or the tumour microenvironment probably represents another major culprit in converting DCs into tolerogenic APCs. DCs exposed to IL-10 have strongly reduced stimulatory capacities, while inducing a state of alloantigen-specific anergy in both primed and naı¨ve CD45RAþ CD8þ T cells. In contrast to optimally stimulated CD8þ T cells, anergic tyrosinase-specific CD8þ T cells, after co-culture with peptide-pulsed IL-10-treated DCs, fail to lyse tyrosinase-expressing melanoma cells [11]. IL-10 is also likely to represent a key factor in the maintenance of peripheral tolerance. IL-10 can induce the differentiation of T regulatory cells that can mediate antigen-specific tolerance in experimental models of autoimmunity and transplantation [12]. Growth of tumours in patients itself implies host unresponsiveness, however, the question of whether this is the result of true anergy to tumour antigens or simply a failure to recognize these antigens is largely unknown. A fine understanding of the subtle mechanisms of DC defects
that result in a lack of efficient immune responses would enable deciphering some of the mechanisms of tumour immune escape [13], paving the way to new DC-based therapeutic approaches or pharmacological manipulation of DC-mediated immunity. References 1 Coventry, B. and Heinzel, S. (2004) CD1a in human cancers: a new role for an old molecule. Trends Immunol. 25, 242 – 248 2 Cella, M. et al. (1999) Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat. Med. 5, 919 – 923 3 Horny, H.P. et al. (1987) Immunocytology of plasmacytoid T cells: marker analysis indicates a unique phenotype of this enigmatic cell. Hum. Pathol. 18, 28– 32 4 Facchetti, F. et al. (1989) Plasmacytoid monocytes (so-called plasmacytoid T cells) in Hodgkin’s disease. J. Pathol. 158, 57 – 65 5 Vermi, W. et al. (2003) Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas. J. Pathol. 200, 255– 268 6 Zou, W. et al. (2001) Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat. Med. 7, 1339 – 1346 7 Hartmann, E. et al. (2003) Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer. Cancer Res. 63, 6478 – 6487 8 Mohty, M. et al. (2002) Low blood dendritic cells in chronic myeloid leukaemia patients correlates with loss of CD34þ/CD382 primitive haematopoietic progenitors. Br. J. Haematol. 119, 115 – 118 9 Mohty, M. et al. (2001) Circulating blood dendritic cells from myeloid leukemia patients display quantitative and cytogenetic abnormalities as well as functional impairment. Blood 98, 3750 – 3756 10 Fonteneau, J.F. et al. (2003) Activation of influenza virus-specific CD4þ and CD8þ T cells: a new role for plasmacytoid dendritic cells in adaptive immunity. Blood 101, 3520– 3526 11 Steinbrink, K. et al. (1999) Interleukin-10-treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8þ T cells resulting in a failure to lyse tumor cells. Blood 93, 1634– 1642 12 Roncarolo, M.G. et al. (2001) Differentiation of T regulatory cells by immature dendritic cells. J. Exp. Med. 193, F5 – F9 13 Mohty, M. et al. (2002) Leukemic dendritic cells: potential for therapy and insights towards immune escape by leukemic blasts. Leukemia 16, 2197– 2204 1471-4906/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.it.2004.05.005
| Letter Response
Reply to Mohty et al.: Dysfunctional DC subgroups in human cancers Brendon J. Coventry and Susanne Heinzel Adelaide Melanoma Unit, Breast-Endocrine and Surgical Oncology Unit; and Tumour Immunology Laboratory, Department of Surgery, University of Adelaide, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia
Recent data indicate that dendritic-cell (DC) subgroups are dysfunctional in human cancers. The mechanisms for this are currently unclear. Mohty et al. raise a number of interesting issues in their accompanying letter related to Corresponding author: Brendon J. Coventry ([email protected]). Available online 17 June 2004 www.sciencedirect.com
the types and possible functions of different sub-groups of DCs in human cancers [1]. These comments are timely and highlight the possible role of DCs in the activation or inhibition of the antitumour immune response. ‘Plasmacytoid’ DCs (PDCs) appear to have an important part in the regulation of antitumour immune responses. PDCs can expand antigen-specific T cells [2], induce