epithelial cells. Eotaxins signal through CCR3 receptor, which is expressed at high levels on eosinophils and Th2 cells. Cellular sources of eotaxin include fibroblasts, endothelial cells, eosinophils, and lymphocytes.
PTCLs most commonly associated with eosinophilia include primary CTCL, AITL, and ATLL. Approximately 15–20% of patients with mycosis fungoides and up to 75% of those with Sézary syndrome develop blood eosinophilia and show numerous eosinophils within cutaneous lymphoma infiltrates. Eosinophilia in mycosis fungoides and Sézary syndrome, is related to the Th2 nature of the lymphoma cells, which produce IL4, IL5, and IL13. The recruitment of eosinophils to the skin is mediated by chemoattractants produced by the lymphoma cells but also possibly by other cell types. Indeed, IL4‐producing lymphoma cells induce increased expression of eotaxin‐3/CCL26 by keratinocytes, endothelial cells, and fibroblasts [89]. In cutaneous ALCL as well lymphomatoid papulosis (type A), a reactive inflammatory infiltrate may be found within the tumor, and eosinophils may be detected in a substantial proportion of patients occasionally representing the predominant cell type. CD30+ tumor cells isolated from skin biopsies with cutaneous ALCL have been shown to coexpress CCR3 and IL4, and eotaxin in conjunction with surrounding cells, indicating that they contribute to eosinophilic infiltrates [90].
The functional role of eosinophils within the tumor microenvironment remains poorly characterized. Eosinophils also produce IL5 and since they also express the cognate receptor, autocrine activation is possible. Clinical and experimental investigations have shown that eosinophils can function as antigen‐presenting cells and can promote the proliferation of effector T cells. In addition, eosinophils are able to produce an array of cytokines (IL2, IL4, IL6, IL10, and IL12) capable of promoting T‐cell proliferation, activation, and influencing Th1–Th2 polarization, thereby regulating tumor cell growth and expansion [91].
Underlying Factors Favoring the Tumor Transformation
Mechanisms driving cancer initiation and genomic instability are unclear in PTCL. Indeed, in contrast to other cancers where critical susceptibilities have been identified, such as tobacco or human papillomavirus in lung or cervix carcinomas, or the importance of AID in B‐cell malignancies, few factors are known to predispose to PTCL.
Viruses
Two viruses with oncogenic properties, HTLV1 and EBV play a causal role in the development of NK‐ or T‐cell lymphoproliferations.
Human T‐cell Leukemia Virus Type 1
HTLV1, also known as human T‐lymphotropic virus type 1, was the first exogenous human deltaretrovirus discovered [92]. The 9‐kb genome of HTLV1 encodes the gag, pol, and env structural proteins, plus accessory and regulatory proteins at the 3′ end of the genome (tax, rex, p12, p21, p30, p13, and HBZ) that play an important role in the regulation of viral replication, persistence, and leukemogenesis [93].
HTLV1 infection causes ATLL, after a long latency of about 50 years after mother‐to‐child transmission. ATLL is a disease exemplifying an infectious agent‐driven lymphoma and multistep lymphomagenesis. Only a small fraction of infected individuals will ever develop ATLL, while the majority of infected individuals will remain asymptomatic carriers. Given the long latency period and low incidence of ATLL development in HTLV1‐infected individuals, it is postulated that other events are required for transformation, besides the role of HTLV1 infection itself, which is supported by its constant presence and the monoclonal integration of a single viral copy in the majority of cases. It is estimated that an asymptomatic HTLV1‐positive individual carries between 10e4 to 10e5 distinct clones of HTLV1‐infected T cells and each clone is distinguished by a unique site of integration of the provirus into the host genome [94]. Conversely, a single dominant clone is found among a background of hundreds of clones in patients with ATLL [95]. The proviral integration site of HTLV1 into the host genome is strongly biased toward certain transcription factor binding sites, notably STAT1, TP53, and HDAC6 [96].
Two viral proteins are implicated in oncogenesis: the transactivator protein (TAX) that is critical for T‐cell proliferation mainly via activation of NF‐κB and AP‐1 pathways, and is involved in tumor initiation; and the antisense gene product basic leucine zipper protein (HBZ) that may serve as a tumor promoter and play a role in tumor maintenance [97]. However, most neoplastic cells do not express oncogenic viral TAX, and only express HBZ. The other genomic events identified to drive disease pathogenesis include alterations altering in T‐cell receptor‐NF‐κB signaling, T‐cell trafficking (e.g. CCR4, CCR7), and immunosurveillance, as described above [46].
Epstein–Barr Virus
EBV, also known as HHV4 (human herpesvirus type 4), is found in approximately 95% of the adult population worldwide. B cells are the main target of EBV infection but EBV can also infect epithelial cells, mainly in the nasopharyngeal region, which is thought to occur during viral reactivation. In line with its capacity to infect epithelial cells and B cells, EBV is associated with nasopharyngeal carcinoma and several B‐cell malignancies, notably endemic Burkitt lymphoma and B‐cell lymphoproliferative disorders in immunosuppressed patients. EBV infection is also considered as a sine qua none characteristic of ENKTL and aggressive NK‐cell leukemia as well as in other rare disorders such as systemic EBV+ T‐lymph or hydroa vacciniforme‐like lymphoproliferative disorder, two diseases occurring mainly in children and adolescents from Asia and Central and South America.
In addition to these EBV‐positive T‐cell neoplasms where EBV genome is found in virtually all neoplastic cells, in other instances, notably Tfh lymphomas, EBV may be detected in a smaller subset of the tumor cells corresponding to reactive B cells. In ENKTL, the tumor most commonly occurs in sites of primary EBV infection. Since T and NK cells do not normally harbor CD21 which is the membrane receptor mediating EBV entry into the cells, the mechanism proposed is the infection of resident NK (or T) after acquisition of CD21 through “trogocytosis” or via the direct transfer of viral episomes [98, 99].
In ENKTL, like in most EBV‐associated malignancies, EBV infection expresses a type II latency program, which comprises several latent proteins (LMP1, EBNA, and LMP2). The latent protein best characterized with respect to oncogenic properties is LMP1, a signaling protein that imitates a constitutively active tumor necrosis factor receptor, and activates mitogen‐activated protein kinases and STAT and NF‐κB transcription factors in B cells [100]. LMP1 increases proliferation and survival of the infected cells. Similarly, while a role for EBV in ENKTL pathogenesis is highly suspected, its precise oncogenic functions in NK and T cells are not fully deciphered. An enrichment of the NF‐κB pathway is observed in ENKTL and activated EBV‐infected NK cells, and produce IL2 and IL9, which are two cytokines important for NK cell activation and proliferation.
The immunosuppressive background in ENKTL, due notably to IL10, may promote tumor expansion as well as expression of the oncogenic protein LMP1 [52]. The proliferating EBV‐infected NK cells might first manifest as a chronic active EBV infection. During their expansion, they further acquire other genomic alterations such as mutations, involving RNA helicases (DDX3X), tumor suppressors (TP53), JAK–STAT pathway molecules (JAK3, STAT3, STAT5B), and epigenetic modifiers (MLL2, ARID1A, EP300, and ASXL3), as well as constitutive activation of growth factors and/or transcription factors, ultimately resulting in a full blown ENKTL. Additionally, genome‐wide association studies have identified a significant association to constitutive genetic variants like HLA‐DPB1 on 6p21.3, and IL18RAP on 2q12.1 indicating baseline susceptibility of certain individuals for the development of ENKTL [101, 102].
Chronic Antigenic Stimulation
Chronic antigen stimulation resulting in chronic B‐cell receptor or TCR activation, can promote lymphomagenesis. This concept is supported by the observation of biases in the B‐cell receptor repertoire in B‐cell malignancies, but most importantly the observation of response or cure after Helicobacter pylori or HCV eradication in some B‐cell malignancies, such as marginal zone lymphomas of splenic