Key Points Alternatively polarized macrophages are abundant constituents of the tumor microenvironment in T-cell lymphoproliferative disorders. GATA-3 expression identifies a subset of PTCL, NOS with a distinct cytokine profile and inferior survival.
IntroductionTumorigenesis is associated with a wide array of both genetic and epigenetic changes that give rise to tumor-associated antigens capable of eliciting a host antitumor immune response. Although host immune surveillance may prevent tumor outgrowth during the earliest stages of tumor growth, locally invasive or metastatic tumors must evade host immunity. 1 Immune escape is not merely a passive process of immune evasion but an active one by which both tumor cells and stromal cells present within the tumor microenvironment actively suppress the antitumor immune response. This distinction between immune evasion and suppression is an important one and may explain the paradoxical observation that many tumor immunotherapy clinical trials, despite eliciting an antitumor immune response, are not associated with a meaningful clinical response. 2 Improved mechanistic understanding of tumor-associated immune suppression is needed if the next generation of immunotherapeutic strategies is to be rationally designed.Malignant cells may suppress host immunity directly, by producing immunoregulatory cytokines or expressing inhibitory ligands on their cell surface. In addition, malignant cells may influence the tumor microenvironment leading to the induction or recruitment of immunoregulatory cells capable of suppressing host immunity. 3 Both myeloid-derived cells (including tumor-associated macrophages, dendritic cells [DCs], and myeloid-derived suppressor cells) and lymphocyte subsets, most notably regulatory T (Treg) cells, present within the tumor microenvironment, collaborate with their malignant counterparts to suppress host immunity. 3,4 The microenvironment's role in promoting tumor growth in nonHodgkin lymphoma (NHL) was recently highlighted by both gene expression profiling and immunohistochemistry-based approaches. [5][6][7] Therapeutic approaches capable of targeting the tumor microenvironment are currently being translated into clinical practice in hematologic malignancies and may be associated with improved outcomes. 8,9 Fundamentally, 2 distinct approaches capable of targeting the tumor microenvironment may be imagined. The first seeks to eliminate immunosuppressive cells present within the tumor microenvironment and is highlighted by recent attempts to eliminate Treg. As different stromal cells may use common immunosuppressive mediators, the alternative approach seeks to identify and neutralize these shared molecular mediators of host immune suppression.Members of the B7 family have emerged as important mediators of host immune suppression. In contrast to B7-1 (CD80) and B7-2 (CD86), which play an important role in T-cell activation and costimulation, the B7 homologs (B7-H, including B7-H1, B7-H2, B7-H3, and B7-H4), which have been described more recently may function as important "coinhibitors" of host T-cell immunity and have been associated with poor clinical outcomes in a variety of human tumors. 10,11 B7-H1, for example, may be inducibly expressed on tumor cells and confer resistance to killing media...
A variety of nonmalignant cells present in the tumor microenvironment promotes tumorigenesis by stimulating tumor cell growth and metastasis or suppressing host immunity. The role of such stromal cells in T-cell lymphoproliferative disorders is incompletely understood. Monocyte-derived cells (MDCs), including professional antigen-presenting cells such as dendritic cells (DCs), play a central role in T-cell biology. Here, we provide evidence that monocytes promote the survival of malignant T cells and demonstrate that MDCs are abundant within the tumor microenvironment of T cell-derived lymphomas. Malignant T cells were observed to remain viable during in vitro culture with autologous monocytes, but cell death was significantly increased after monocyte depletion. Furthermore, monocytes prevent the induction of cell death in T-cell lymphoma lines in response to either serum starvation or doxo-rubicin, and promote the engraftment of these cells in nonobese diabetic/severe combined immunodeficient mice. Mono-cytes are actively recruited to the tumor microenvironment by CCL5 (RANTES), where their differentiation into mature DCs is impaired by tumor-derived interleukin-10. Collectively, the data presented demonstrate a previously unde-scribed role for monocytes in T-cell lym-phoproliferative disorders. (Blood. 2009;
Current pathologic criteria cannot reliably distinguish cutaneous anaplastic large cell lymphoma from other CD30-positive T-cell lymphoproliferative disorders (lymphomatoid papulosis, systemic anaplastic large cell lymphoma with skin involvement, and transformed mycosis fungoides). We previously reported IRF4 (interferon regulatory factor-4) translocations in cutaneous anaplastic large cell lymphomas. Here, we investigated the clinical utility of detecting IRF4 translocations in skin biopsies. We performed fluorescence in situ hybridization for IRF4 in 204 biopsies involved by T-cell lymphoproliferative disorders from 182 patients at three institutions. Nine of forty-five (20%) cutaneous anaplastic large cell lymphomas and 1 of 32 (3%) cases of lymphomatoid papulosis with informative results demonstrated an IRF4 translocation. Remaining informative cases were negative for a translocation (7 systemic anaplastic large cell lymphomas; 44 cases of mycosis fungoides/Sézary syndrome (13 transformed); 24 peripheral T-cell lymphomas, not otherwise specified; 12 CD4-positive small/medium-sized pleomorphic T-cell lymphomas; 5 extranodal NK/T-cell lymphomas, nasal type; 4 gamma-delta T-cell lymphomas; and 5 other uncommon T-cell lymphoproliferative disorders). Among all cutaneous T-cell lymphoproliferative disorders, fluorescence in situ hybridization for IRF4 had a specificity and positive predictive value for cutaneous anaplastic large cell lymphoma of 99% and 90%, respectively (p=0.00002, Fisher’s exact test). Among anaplastic large cell lymphomas, lymphomatoid papulosis, and transformed mycosis fungoides, specificity and positive predictive value were 98% and 90%, respectively (p=0.005). Fluorescence in situ hybridization abnormalities other than translocations and IRF4 protein expression were seen in 13% and 65% of cases, respectively, but were non-specific with regard to T-cell lymphoproliferative disorder subtype. Our findings support the clinical utility of fluorescence in situ hybridization for IRF4 in the differential diagnosis of T-cell lymphoproliferative disorders in skin biopsies, with detection of a translocation favoring cutaneous anaplastic large cell lymphoma. Like all fluorescence in situ hybridization studies, IRF4 testing must be interpreted in the context of morphology, phenotype, and clinical features.
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