Macrophages in T cell/histiocyte rich large B cell lymphoma strongly express metal-binding proteins and show a bi-activated phenotype

Abstract

Abundant macrophage infiltration in tumors often correlates with a poor prognosis. T cell/histiocyte rich large B cell lymphoma (THRLBCL) is a distinct aggressive B cell lymphoma entity showing a high macrophage content. To further elucidate the role of tumor-associated macrophages in THRLBCL, we performed gene expression profiling of microdissected histiocyte subsets of THRLBCL, nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), Piringer lymphadenitis, sarcoidosis, nonspecific lymphadenitis and monocytes from peripheral blood. In a supervised principal component analysis, histiocytes from THRLBCL were most closely related to epithelioid cells from NLPHL, with both types of cells expressing genes related to proinflammatory and regulatory macrophage activity. Moreover, histiocytes from THRLBCL strongly expressed metal-binding proteins like MT2A, by which histiocytes of THRLBCL can be distinguished from the other histiocyte subsets investigated. Interestingly, the validation at the protein level showed a strong expression of TXN, CXCL9, MT2A and SOD2 not only in macrophages of THRLBCL but also in the tumor cells of NLPHL and classical Hodgkin lymphoma (cHL). Overall, the present findings indicate that macrophages in the microenvironment of THRLBCL have acquired a distinct gene expression pattern that is characterized by a mixed M1/M2 phenotype and a strong expression of several metal binding proteins. The microenvironments in NLPHL and THRLBCL appear to have a similar influence on the macrophage phenotype. The high expression of metal binding proteins in histiocytes of THRLBCL may be diagnostically useful, but a potential pathophysiological role remains to be identified.

Nodular Lymphocyte Predominant Hodgkin Lymphoma and T cell/Histiocyte Rich Large B Cell Lymphoma Endpoints of a Spectrum of one Disease?

“…We cannot exclude that this result is influenced by technical limitations, like a strong amplification of the RNA before array hybridization, causing loss of some differentially expressed genes. However, applying the same technique, we obtained numerous and up to 21-fold differentially expressed genes in another study of microdissected cells [12]. Both the unsupervised hierarchical clustering as well as the principal component analysis revealed that there is often more heterogeneity in global gene expression between two cases of one of the three lymphoma entities analyzed than between cases of different entities.…”

“…Both BAT3/ BAG6 as well as UBD/FAT10 expression was shown to be increased during inflammatory response [21,43]. This may be caused by the release of proinflammatory factors from macrophages of THRLBCL [12]. Moreover, HIGD1A, an important player in the maintenance of normal mitochondrial function in hypoxia [17,44,45], was expressed in a subset of cases.…”

“…Methods S1), 9 cases of THRLBCL-like NLPHL (pattern E) and 11 cases of THRLBCL were laser microdissected as previously described [12]. For comparison to tumor cells, CD77…”

A novel immunohistochemical classifier to distinguish Hodgkin lymphoma from ALK anaplastic large cell lymphoma

“…Moreover, Hodgkin and Reed-Sternberg cells are known to express several additional markers usually expressed by antigenpresenting cells. [46][47][48] Although Hodgkin and ReedSternberg cells have usually lost their B-cell phenotype, they have maintained the features for an interaction with T cells, which is not observed in the tumor cells of ALK À anaplastic large cell lymphoma. Interestingly, Hodgkin lymphoma cases with granzyme B expression were less frequently positive for MDC/CCL22 and CD83 than conventional classical Hodgkin lymphoma cases.…”

“…Whole tissue sections were stained for CD83, MDC/CCL2, TUBB2B, STAT3, and CAPN2 using the Peroxidase-FLEX EnVision Kit (Dako) as described previously. 22,23 The antibodies used, dilutions, and providers are listed in Table 2. Antigen unmasking was performed for 3 min in a pressure cooker or microwave in Tris-EDTA at pH 8.0 or citrate buffer at pH 6.0.…”