The novel immunosuppressive enzyme IL4I1 is expressed by neoplastic cells of several B-cell lymphomas and by tumor-associated macrophages

Abstract

We previously reported a strong IL4I1 gene expression in primary mediastinal B-cell lymphoma (PMBL) and recently identified the protein as a secreted L-phenylalanine oxidase, physiologically expressed by myeloid cells, which inhibits T-cell proliferation in vitro. Here, we analyzed the pattern of IL4I1 protein expression in 315 human lymphoid and nonlymphoid malignancies. Besides PMBL, IL4I1 expression in tumors was very frequent. IL4I1 was detected in tumorassociated macrophages from most of the tumors and in neoplastic cells from follicular lymphoma, classic and nodular lymphocyte predominant Hodgkin lymphomas and small lymphocytic lymphoma, three of which are germinal center derived. IL4I1-positive tumor cells were also detected in rare cases of solid cancers, mainly mesothelioma. The enzymatic activity paralleled protein expression, suggesting that IL4I1 is functional in vivo. Depending on the tumor type, IL4I1 may impact on different infiltrating lymphocyte populations with consequences on tumor evolution. In the particular case of follicular lymphoma cells, which are susceptible to antitumor cytotoxic T cells killing but depend on interactions with local T helper cells for survival, a high level of IL4I1 expression seems associated with the absence of bone marrow involvement and a better outcome. These findings plead for an evaluation of IL4I1 as a prognosis factor.

Follicular lymphoma cell niche: identification of a preeminent IL-4-dependent TFH–B cell axis

“…The overexpression of IL-4 within FL microenvironment was thus associated to a strong activation of malignant B cells. In agreement, we observed that both IL4I1 and HOXC4, two previously described IL-4 target genes, 21,23 belonged to the 886-PS FL_B list (Supplementary Figure S3A). Similarly, GCET2/HGAL, another gene reported as induced by IL-4 in normal B cells and in some malignant B-cell lines, 24 was significantly upregulated in FL_B compartment (Supplementary Figure S3B) even if it was excluded from the microarray analysis by the initial standard deviation-based filtering.…”

“…21 Briefly, after appropriate antigen retrieval with microwave heating in high pH Target Retrieval Solution (DakoCytomation, Glostrup, Denmark), deparaffinized tissue sections were stained with anti-P-STAT6/Tyr641 antibody (polyclonal rabbit; dilution 1/30; Cell Signaling Technology, Danvers, MA, USA), using an indirect immunoperoxidase method (ImmPRESS anti-rabbit; Vector Laboratories, Burlingame, CA, USA) and diaminobenzidine (Vector Laboratories) as chromogen. For double immunostaining, slides were first incubated with anti-CD20 (clone L26, Dako), anti-CD5 (clone 4C7, Novocastra, Newcastle, UK) or anti-PD1 (clone NAT, Abcam, Cambridge, UK) monoclonal antibody and labeled using the alkaline phosphatase-conjugated avidin biotinylated enzyme complex procedure (Vector Laboratories).…”

DC-SIGN–expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma

“…26,49 Recently, BCR inhibitors have gained considerable interest because of their effectiveness in several B-cell lymphoma subtypes. Interestingly, their efficacy relies not only on the direct blockade of BCR-mediated B-cell survival but also on their capacity to abrogate the BCR-dependent activation of integrins and increase of chemotaxis.…”

The host-tumor interface in B-cell non-Hodgkin lymphoma: A new world to investigate

“…Similarly, high levels of the chemokine receptor CCR1 transcript, known to be an activation marker for monocytes, were found to be associated with a poor outcome in follicular lymphoma [14]. By contrast, the IL4I protein encoding secreted L-phenylalanine oxidase, which inhibits T-cell proliferation in vitro, was also found to be expressed in follicular lymphoma macrophages, where it may be associated with favorable features [15]. Using a microarray approach, the scavenger macrophage receptor with collagenous structure (MARCO), together with EPHA-1, a tyrosine kinase involved in transepithelial migration (expressed in granulocytes), and the transcription factor SMAD-1 (expressed in vascular endothelium) were suggested as prognostic markers in follicular lymphoma [16]: low SMAD-1 and MARCO expression were associated with better progression-free survival in a small patient cohort receiving chemotherapy and rituximab.…”