In line with the growing Th2-bias and malignant T cell expression of factors such as PGE2, IL-10, and high-mobility group BOX-1 protein (HMGB1), the infiltration of mast cells, eosinophils, and tumor-associated macrophages (TAMs) with an M2 phenotype, typically increases during CTCL progression [
89,
122‐
127]. A high degree of infiltration by each of these immune subsets has been linked to poor prognosis, suggesting that the malignant T cells may foster a pro-tumorigenic environment by promoting accumulation of granulocytes and TAMs [
122,
123,
127]. Accordingly, Rabenhorst et al. demonstrated that mast cells in CTCL lesions generally exhibit a degranulated phenotype, and that their numbers correlate with the microvessel density [
122]. Supernatant from activated mast cells was further able to promote the proliferation of malignant CTCL cells in vitro, and depletion of mast cells in a murine T cell lymphoma model inhibited tumor growth, strongly supporting that mast cells play a pro-tumorigenic role in CTCL [
122]. In a similar manner, eosinophils often display an activated phenotype and express IL-5 in CTCL skin lesions, indicating that they release inflammatory factors into the tumor microenvironment that may aggravate the disease [
123]. Indeed, accumulation of eosinophils in blood and lesional skin of CTCL patients has not only been associated with poor prognosis but also with increased pruritus [
6]. Activated eosinophils can, in addition to IL-5, release high levels of IL-4 and IL-13 as well as angiogenic factors. This raises the possibility that malignant T cells, through the attraction and activation of eosinophils, may fuel their own growth indirectly by boosting neovascularization and a deregulated Th2 response [
128]. Marked infiltration of neutrophils is only occasionally seen in CTCL, but detection of neutrophilic dermatoses has been associated with an aggressive disease course [
70,
74]. As already mentioned, L-17A and IL-17F are expressed in the lesional skin in a subset of CTCL patients and known to stimulate recruitment of neutrophils [
62,
70,
71]. High expression of IL-17A has, accordingly, been associated with neutrophilic infiltration into CTCL lesions; whether it is also the case for IL-17F remains to be investigated [
70]. Malignant T cells derived from some patients have the capacity to express IL-17A and/or IL-17F via a Jak3/Stat3/Stat5-dependent mechanism but do not express the Th17-linage transcription factor, RORc, or display a characteristic Th17-phenotype [
62,
71,
76,
129]. Therefore, expression of IL-17A and IL-17F by the malignant T cells is probably not reflective of Th17 origin, or acquisition of a full-fledged Th17 phenotype, but rather a consequence of dysregulated signaling. Several cell types, including Th17 cells, mast cells and neutrophils are also known to produce IL-17 cytokines and it is likely that they also provide a significant source of IL-17A and IL-17F in some lesions. Accordingly, skin-infiltrating neutrophils and mast cells have been reported to stain positive for IL-17 in CTCL patients with neutrophilic dermatoses [
72].
M2-like TAMs are generally believed to contribute to tumorigenesis by promoting angiogenesis, matrix remodeling and inhibition of adaptive immunity [
131]. In agreement with the notion that the malignant T cells drive the accumulation of M2-like TAMs during the clinical course of CTCL, M2-like macrophages were found to be abundant within the tumor microenvironment, but not in the spleen, in a CTCL mouse model [
126]. Furthermore, effective treatment of CTCL patients resulting in decreased numbers of tumor cells was shown to be accompanied by a strong decrease of dermal TAMs in the lesional skin [
127]. TAMs express CCL18 and MMP9 in CTCL lesions, and clodronate-mediated depletion of M2-like macrophages in a mouse model of CTCL inhibited angiogenesis, lymphangiogenesis, and tumor development. Collectively, these results implicate M2-like TAMs in vascularization, chemotaxis, tissue remodeling, and tumor growth in CTCL [
51,
126,
132].
The malignant T cells also display aberrant release of cytokines and other factors, such as vascular endothelial growth factor (VEGF), prostaglandins, and lymphotoxins, which promote activation of endothelial cells and fibroblasts, thereby stimulating angiogenesis via both direct and indirect mechanisms [
62,
70,
71,
81,
119,
133,
134]. For example, the malignant T cells can trough release of VEGF-A and lymphotoxin α induce enhanced endothelial sprouting in vitro and further trigger fibroblast expression of VEGF-C and angiogenesis in vivo
, supporting the concept that the malignant T cells orchestrate profound changes in the tumor microenvironment [
133,
135]. Indeed, the malignant T cells strongly impacted skin structure, as well as keratinocyte activation and proliferation, in an organotypic skin model and a xenograft CTCL mouse model [
116]. Hence, malignant T cells and their supernatants triggered Jak and MAPK activation in keratinocytes, downregulation of differentiation markers such as keratin 10 and involucrin, epidermal hyperproliferation, disorganized keratinocyte stratification, and decreased barrier formation, thus mimicking many features seen in CTCL lesions [
116]. In conclusion, accumulating evidence indicates that the malignant T cells, via interactions with stromal and benign immune cells, drive the disease stage-related inflammatory changes observed in CTCL.