Abstract
Both tumor-associated neutrophils (TAN) and cancer-associated fibroblasts (CAFs) display specific phenotypic and functional features and contribute to tumor cell niche. However, their bidirectional crosstalk has been poorly studied, in particular in the context of hematological malignancies. Follicular lymphomas (FL) and diffuse large B-cell lymphomas (DLBCL) are two germinal center-derived lymphomas where various cell components of infiltrating microenvironment, including TAN and CAFs, have been demonstrated to favor directly and indirectly malignant B-cell survival, growth, and drug resistance. We show here that, besides a direct and contact-dependent supportive effect of neutrophils on DLBCL B-cell survival, mediated through the BAFF/APRIL pathway, neutrophils and stromal cells cooperate to sustain FL B-cell growth. This cooperation relies on an overexpression of IL-8 by lymphoma-infiltrating stromal cells that could thereafter efficiently promote neutrophil survival and prime them to neutrophil extracellular trap. Conversely, neutrophils are able to activate stromal cells in a NF-κB-dependent manner, inducing their commitment towards an inflammatory lymphoid stroma phenotype associated with an increased capacity to trigger malignant B-cell survival, and to recruit additional monocytes and neutrophils through the release of CCL2 and IL-8, respectively. Altogether, a better understanding of the lymphoma-supporting effects of neutrophils could be helpful to design new anti-tumor therapeutic strategies.
Highlights
Tumorigenesis is widely recognized as a noncell autonomous process depending on the continuous active crosstalk between malignant cells and various stromal and immune cell subsets of their surrounding microenvironment
We explored the direct effect of neutrophils on primary malignant B cells obtained from Follicular lymphomas (FL) and diffuse large B-cell lymphomas (DLBCL) including the two major molecular subtypes have been defined in this disease, the germinal center (GC) B cell-like (GCB) and the non-GCB DLBCL that differ by their response to chemotherapy and cure rate [29]
We highlighted for the first time both direct and indirect tumor promoting effects of neutrophils in GC-derived B-cell lymphomas, a group of diseases in which Tumor infiltrating neutrophils (TAN) have been poorly studied even if microenvironment is supposed to play a key role
Summary
Tumorigenesis is widely recognized as a noncell autonomous process depending on the continuous active crosstalk between malignant cells and various stromal and immune cell subsets of their surrounding microenvironment. TAN have been recently shown to exert both proand antitumor activities, including triggering of genomic instability, angiogenesis, immunosuppression, and tumor cell metastasis on the one hand versus direct cytotoxic www.impactjournals.com/oncotarget effect and recruitment or activation of other effectors of innate and adaptive antitumor immunity on the other hand [3]. Resident mesenchymal stromal cells (MSCs) are believed to be the major precursors of CAFs in situ and to acquire their tumor promoting properties after exposition to tumorderived activating stimuli. Whereas their impact on neutrophil activation remains controversial, bone marrow (BM)-MSCs have been repeatedly shown to sustain neutrophil survival, in particular following activation by inflammatory stimuli and TLR ligands [7, 8]. Few data are available concerning reciprocal interactions between TAN and CAFs in solid and hematological malignancies
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