Defective Stromal Remodeling and Neutrophil Extracellular Traps in Lymphoid Tissues Favor the Transition from Autoimmunity to Lymphoma

Abstract

Altered expression of matricellular proteins can become pathogenic in the presence of persistent perturbations in tissue homeostasis. Here, we show that autoimmunity associated with Fas mutation was exacerbated and transitioned to lymphomagenesis in the absence of SPARC (secreted protein acidic rich in cysteine). The absence of SPARC resulted in defective collagen assembly, with uneven compartmentalization of lymphoid and myeloid populations within secondary lymphoid organs (SLO), and faulty delivery of inhibitory signals from the extracellular matrix. These conditions promoted aberrant interactions between neutrophil extracellular traps and CD5 + B cells, which underwent malignant transformation due to defective apoptosis under the pressure of neutrophil-derived trophic factors and NF-κB activation. Furthermore, this model of defective stromal remodeling during lymphomagenesis correlates with human lymphomas arising in a SPARC-defective environment, which is prototypical of CD5 + B-cell chronic lymphocytic leukemia (CLL). SIGNIFICANCE:These results reveal the importance of stromal remodeling in SLO to accommodate autoimmune lymphoproliferation while preventing lymphomagenesis. Our fi ndings reveal a link between SPARC, collagen deposition, and the engagement of the immune-inhibitory receptor LAIR-1 on neutrophils, neutrophil cell death via NETosis, and the stimulation of CD5 + B-cell proliferation. Moreover, we show that SPARC defi ciency promotes CD5 + B-cell lymphomagenesis and is correlated with CLL in humans. Cancer Discov; 4(1);

Persistent Immune Stimulation Exacerbates Genetically Driven Myeloproliferative Disorders via Stromal Remodeling

“…Human and murine bone marrow histology, immunohistochemistry, and immunofluorescence Histologic, histochemical, and immunofluorescence analyses of murine and human bone marrow samples were performed as previously described (2,5) and detailed in the Supplementary Data. For in situ histopathologic analyses of human bone marrow specimens, the bone marrow biopsies from 12 patients with autoimmunity-associated peripheral cytopenias were selected from the archives of the Department of Hematology, University of Foggia, Foggia, Italy, and the Department of Health Sciences, University of Palermo, Palermo, Italy.…”

“…A key regulator of bone marrow stromal changes is the secreted protein acidic and rich in cysteine (SPARC; ref. 4), a matricellular protein in which up-and downregulation has been associated with hematologic neoplasms (2,5).…”

“…A defective ECM organization resulting from SPARC deficiency favors the over-activation of myeloid cells (8) and granulocyte immunogenic death via the formation of neutrophil extracellular traps (NET; ref. 5). NETotic death is characterized by the expression of IFN response-related transcriptional programs associated with the induction of inflammation and exacerbation of autoimmune disease, in which NETs contribute as sources of autoantigens and costimulatory signals (9)(10)(11)(12)(13).…”

Immunostimulatory Monoclonal Antibodies and Immunomodulation: Harvesting the Crop

“…matrix by analyzing knockout mice for SPARC, a protein essential for collagen assembly (25). Dr. M. Colombo's team observed critical interactions of the collagen cellular matrix for shaping the antitumor immune response, which resemble the way SPARC contributes to the germinal center reaction and to all the other stroma-dependent phases of B-cell development, also discovered by Dr. M. Colombo.…”

Optimising intratumoural treatment of head and neck squamous cell carcinoma mouse models with EBC-46

“…Initially, these were known to have antimicrobial effects but NETs are now proposed to facilitate either a pro or anti-tumourigenic microenvironment. Interestingly, NET production (NETosis) can also be induced by phorbol esters, such as PMA [99]. …”