- Email: [email protected]
Cutaneous T-Cell Lymphoma: The Yin and Yang of Inflammation and Neoplasia
MEETING REPORT
Cutaneous T-Cell Lymphoma: The Yin and Yang of Inflammation and Neoplasia Xuesong Wu1 and Sam T. Hwang1 The Journal of Investigative Dermatology Symposium (2015) 17, 34–35; doi:10.1038/jidsymp.2015.10
Cutaneous T-cell lymphoma (CTCL) is acknowledged to be a neoplastic process with clonal malignant T cells that can metastasize to regional lymph nodes and, occasionally, to visceral organs (Hwang et al., 2008). Similar to other solid tumors, large, bulky CTCL tumors can be both disfiguring as well as serve as portals for infection if they begin to ulcerate. Moreover, in contrast, CTCL cells are immune cells themselves, often originate from CD4 þ T cells in mycosis fungoides (the most common form of CTCL) and respond to immunomodulatory agents such as corticosteroids and imiquimod (Dummer et al., 2003). CTCL tumors develop in a complex immunological environment that comprises macrophages, dendritic cells, innate immune cells, and other T cells (Kim et al., 2005). Recent clinical data suggest that
the presence of certain immune cells (i.e., CD8 þ T cells) in the skin can correlate with a better prognosis in CTCL and that others (i.e., macrophages) correlate with a poor prognosis (Sugaya et al., 2012). Our recent work has focused on the role of macrophages in a unique murine model of CTCL (Wu et al., 2011; Wu et al., 2014). In this model, we inject MBL2 T lymphoma cells into the ear skin of wild-type C56BL/6 mice (Figure 1). Skin lymphoma tumors only occur if a well-known contact sensitizer, di-nitro-fluoro-benzene (DNFB), is topically applied to skin immediately after inoculation of MBL2 T cells into skin. We have shown that even a single application of DNFB results in activation of IL-1b in the skin and that recombinant IL-1b can partially replace DNFB treatment as an enabler of tumor growth
a DNFB
DNFB
14 Days
MBL2
Vehicle
2 Days
b
in this model (Wu et al., 2011). Of note, corticosteroids, well known to be firstline treatment for human mycosis fungoides, block the development of tumors in this murine model. F4/80 þ macrophages and Gr-1 þ neutrophils are the predominant immune cell populations that infiltrate the tumor over the 2 weeks that are required for tumor formation. Interestingly, depletion of neutrophils using anti-Gr-1 antibodies has no effect on tumor development (Wu et al., 2011). Using an agent, clodronate liposomes, that depletes (kills) phagocytic cells such as macrophages in skin, however, we show that tumor formation is nearly completely blocked by clodronate treatment. This result suggests that macrophages, or possibly other phagocytic cells, have a key role in supporting tumor development.
MBL2 cells: 4×105 per ear DNFB: Dinitrofluorobenzene, 0.5%, 10 µl per ear
Figure 1. An inflammation-dependent model of skin T-cell lymphoma tumorigenesis. MBL2 T lymphoma cells are inoculated in the ear skin of wild-type C57BL/6 mice and then immediately treated with di-nitro-fluoro-benzene, a well-established contact sensitizer. Histologically high-grade tumors form in DNFB-treated ears within 14 days (adapted from (Wu et al., 2011)).
1
Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
Correspondence: Sam T. Hwang, MD, PhD, E4100 Froedtert Hospital, 9200 W. Wisconsin Avenue, Milwaukee, Wisconsin 53226, USA. E-mail: [email protected]
34
The Journal of Investigative Dermatology Symposium (2015), Volume 17
& 2015 The Society for Investigative Dermatology
X Wu and ST Hwang Yin Yang of CTCL
We have extended our work to show that human CTCL tumors derived from Hut78 cells are also sensitive to clodronate liposome treatment (Wu et al., 2014). Examination of clodronate liposome-treated tumors revealed decreased expression of angiogenic markers and signaling pathways (i.e., STAT3) that have been implicated in human CTCL tumors. Furthermore, we can show that the macrophages found in CTCL tumors are of the M2 phenotype that have been implicated as being protumorigenic in solid cancers (Mantovani et al., 2010). These data provide additional experimental support for recent clinical observations from Hodgkin’s disease and in CTCL that suggest a key role for CD63 þ macrophages in supporting lymphomagenesis (Steidl et al., 2010; Sugaya et al., 2012). Interestingly, clodronate liposomes are not toxic to MBL2 T cells in vitro,
suggesting the possibility of a therapeutic strategy-based regulation of the immune environment. Understanding the fundamental roles of macrophages in tumor development may aid us in developing more effective therapies for CTCL in which we regulate the immune environment instead of directly killing the neoplastic cell, which has been the traditional goal of cytotoxic chemotherapy.
CONFLICT OF INTEREST
The authors state no conflict of interest.
REFERENCES Dummer R, Urosevic M, Kempf W et al. (2003) Imiquimod induces complete clearance of a PUVA-resistant plaque in mycosis fungoides. Dermatology 207:116–8 Hwang ST, Janik JE, Jaffe ES et al. (2008) Mycosis fungoides and sezary syndrome. Lancet 371:945–57
Kim EJ, Hess S, Richardson SK et al. (2005) Immunopathogenesis and therapy of cutaneous T cell lymphoma. J Clin Invest 115:798–812 Mantovani A, Garlanda C, Allavena P (2010) Molecular pathways and targets in cancerrelated inflammation. Ann Med 42:161–70 Steidl C, Lee T, Shah SP et al. (2010) Tumorassociated macrophages and survival in classic hodgkin’s lymphoma. N Engl J Med 362:875–85 Sugaya M, Miyagaki T, Ohmatsu H et al. (2012) Association of the numbers of CD163( þ ) cells in lesional skin and serum levels of soluble CD163 with disease progression of cutaneous T cell lymphoma. J Dermatol Sci 68:45–51 Wu X, Schulte BC, Zhou Y et al. (2014) Depletion of M2-like tumor-associated macrophages delays cutaneous T-cell lymphoma development in vivo. J Invest Dermatol 134:2814–22 Wu X, Sells RE, Hwang ST (2011) Upregulation of inflammatory cytokines and oncogenic signal pathways preceding tumor formation in a murine model of T-cell lymphoma in skin. J Invest Dermatol 131:1727–34
www.jidonline.org
35
Cutaneous T-Cell Lymphoma: The Yin and Yang of Inflammation and Neoplasia Xuesong Wu1 and Sam T. Hwang1 The Journal of Investigative Dermatology Symposium (2015) 17, 34–35; doi:10.1038/jidsymp.2015.10
Cutaneous T-cell lymphoma (CTCL) is acknowledged to be a neoplastic process with clonal malignant T cells that can metastasize to regional lymph nodes and, occasionally, to visceral organs (Hwang et al., 2008). Similar to other solid tumors, large, bulky CTCL tumors can be both disfiguring as well as serve as portals for infection if they begin to ulcerate. Moreover, in contrast, CTCL cells are immune cells themselves, often originate from CD4 þ T cells in mycosis fungoides (the most common form of CTCL) and respond to immunomodulatory agents such as corticosteroids and imiquimod (Dummer et al., 2003). CTCL tumors develop in a complex immunological environment that comprises macrophages, dendritic cells, innate immune cells, and other T cells (Kim et al., 2005). Recent clinical data suggest that
the presence of certain immune cells (i.e., CD8 þ T cells) in the skin can correlate with a better prognosis in CTCL and that others (i.e., macrophages) correlate with a poor prognosis (Sugaya et al., 2012). Our recent work has focused on the role of macrophages in a unique murine model of CTCL (Wu et al., 2011; Wu et al., 2014). In this model, we inject MBL2 T lymphoma cells into the ear skin of wild-type C56BL/6 mice (Figure 1). Skin lymphoma tumors only occur if a well-known contact sensitizer, di-nitro-fluoro-benzene (DNFB), is topically applied to skin immediately after inoculation of MBL2 T cells into skin. We have shown that even a single application of DNFB results in activation of IL-1b in the skin and that recombinant IL-1b can partially replace DNFB treatment as an enabler of tumor growth
a DNFB
DNFB
14 Days
MBL2
Vehicle
2 Days
b
in this model (Wu et al., 2011). Of note, corticosteroids, well known to be firstline treatment for human mycosis fungoides, block the development of tumors in this murine model. F4/80 þ macrophages and Gr-1 þ neutrophils are the predominant immune cell populations that infiltrate the tumor over the 2 weeks that are required for tumor formation. Interestingly, depletion of neutrophils using anti-Gr-1 antibodies has no effect on tumor development (Wu et al., 2011). Using an agent, clodronate liposomes, that depletes (kills) phagocytic cells such as macrophages in skin, however, we show that tumor formation is nearly completely blocked by clodronate treatment. This result suggests that macrophages, or possibly other phagocytic cells, have a key role in supporting tumor development.
MBL2 cells: 4×105 per ear DNFB: Dinitrofluorobenzene, 0.5%, 10 µl per ear
Figure 1. An inflammation-dependent model of skin T-cell lymphoma tumorigenesis. MBL2 T lymphoma cells are inoculated in the ear skin of wild-type C57BL/6 mice and then immediately treated with di-nitro-fluoro-benzene, a well-established contact sensitizer. Histologically high-grade tumors form in DNFB-treated ears within 14 days (adapted from (Wu et al., 2011)).
1
Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
Correspondence: Sam T. Hwang, MD, PhD, E4100 Froedtert Hospital, 9200 W. Wisconsin Avenue, Milwaukee, Wisconsin 53226, USA. E-mail: [email protected]
34
The Journal of Investigative Dermatology Symposium (2015), Volume 17
& 2015 The Society for Investigative Dermatology
X Wu and ST Hwang Yin Yang of CTCL
We have extended our work to show that human CTCL tumors derived from Hut78 cells are also sensitive to clodronate liposome treatment (Wu et al., 2014). Examination of clodronate liposome-treated tumors revealed decreased expression of angiogenic markers and signaling pathways (i.e., STAT3) that have been implicated in human CTCL tumors. Furthermore, we can show that the macrophages found in CTCL tumors are of the M2 phenotype that have been implicated as being protumorigenic in solid cancers (Mantovani et al., 2010). These data provide additional experimental support for recent clinical observations from Hodgkin’s disease and in CTCL that suggest a key role for CD63 þ macrophages in supporting lymphomagenesis (Steidl et al., 2010; Sugaya et al., 2012). Interestingly, clodronate liposomes are not toxic to MBL2 T cells in vitro,
suggesting the possibility of a therapeutic strategy-based regulation of the immune environment. Understanding the fundamental roles of macrophages in tumor development may aid us in developing more effective therapies for CTCL in which we regulate the immune environment instead of directly killing the neoplastic cell, which has been the traditional goal of cytotoxic chemotherapy.
CONFLICT OF INTEREST
The authors state no conflict of interest.
REFERENCES Dummer R, Urosevic M, Kempf W et al. (2003) Imiquimod induces complete clearance of a PUVA-resistant plaque in mycosis fungoides. Dermatology 207:116–8 Hwang ST, Janik JE, Jaffe ES et al. (2008) Mycosis fungoides and sezary syndrome. Lancet 371:945–57
Kim EJ, Hess S, Richardson SK et al. (2005) Immunopathogenesis and therapy of cutaneous T cell lymphoma. J Clin Invest 115:798–812 Mantovani A, Garlanda C, Allavena P (2010) Molecular pathways and targets in cancerrelated inflammation. Ann Med 42:161–70 Steidl C, Lee T, Shah SP et al. (2010) Tumorassociated macrophages and survival in classic hodgkin’s lymphoma. N Engl J Med 362:875–85 Sugaya M, Miyagaki T, Ohmatsu H et al. (2012) Association of the numbers of CD163( þ ) cells in lesional skin and serum levels of soluble CD163 with disease progression of cutaneous T cell lymphoma. J Dermatol Sci 68:45–51 Wu X, Schulte BC, Zhou Y et al. (2014) Depletion of M2-like tumor-associated macrophages delays cutaneous T-cell lymphoma development in vivo. J Invest Dermatol 134:2814–22 Wu X, Sells RE, Hwang ST (2011) Upregulation of inflammatory cytokines and oncogenic signal pathways preceding tumor formation in a murine model of T-cell lymphoma in skin. J Invest Dermatol 131:1727–34
www.jidonline.org
35