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1.
Cancer Res Commun ; 3(3): 420-430, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36923707

RESUMO

Multiple myeloma is characterized by clonal proliferation of plasma cells that accumulate preferentially in the bone marrow (BM). The tumor microenvironment is one of the leading factors that promote tumor progression. Neutrophils and monocytes are a major part of the BM tumor microenvironment, but the mechanism of their contribution to multiple myeloma progression remains unclear. Here, we describe a novel mechanism by which S100A8/S100A9 proteins produced by BM neutrophils and monocytes promote the expansion of megakaryocytes supporting multiple myeloma progression. S100A8/S100A9 alone was not sufficient to drive megakaryopoiesis but markedly enhanced the effect of thrombopoietin, an effect that was mediated by Toll-like receptor 4 and activation of the STAT5 transcription factor. Targeting S100A9 with tasquinimod as a single agent and in combination with lenalidomide and with proteasome inhibitors has potent antimyeloma effect that is at least partly independent of the adaptive immune system. This newly identified axis of signaling involving myeloid cells and megakaryocytes may provide a new avenue for therapeutic targeting in multiple myeloma. Significance: We identified a novel mechanism by which myeloid cells promote myeloma progression independently of the adaptive immune system. Specifically, we discovered a novel role of S100A8/S100A9, the most abundant proteins produced by neutrophils and monocytes, in regulation of myeloma progression via promotion of the megakaryocyte expansion and angiogenesis. Tasquinimod, an inhibitor of S100A9, has potent antimyeloma effects as a single agent and in combination with lenalidomide and with proteasome inhibitors.


Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Megacariócitos/metabolismo , Lenalidomida , Inibidores de Proteassoma , Calgranulina B/metabolismo , Calgranulina A/metabolismo , Microambiente Tumoral
2.
Cancer Res ; 82(19): 3561-3572, 2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36069973

RESUMO

Neutrophils are closely involved in the regulation of tumor progression and formation of premetastatic niches. However, the mechanisms of their involvement and therapeutic regulation of these processes remain elusive. Here, we report a critical role of neutrophil peptidylarginine deiminase 4 (PAD4) in neutrophil migration in cancer. In several transplantable and genetically engineered mouse models, tumor growth was accompanied by significantly elevated enzymatic activity of neutrophil PAD4. Targeted deletion of PAD4 in neutrophils markedly decreased the intratumoral abundance of neutrophils and led to delayed growth of primary tumors and dramatically reduced lung metastases. PAD4-mediated neutrophil accumulation by regulating the expression of the major chemokine receptor CXCR2. PAD4 expression and activity as well as CXCR2 expression were significantly upregulated in neutrophils from patients with lung and colon cancers compared with healthy donors, and PAD4 and CXCR2 expression were positively correlated in neutrophils from patients with cancer. In tumor-bearing mice, pharmacologic inhibition of PAD4 with the novel PAD4 isoform-selective small molecule inhibitor JBI-589 resulted in reduced CXCR2 expression and blocked neutrophil chemotaxis. In mouse tumor models, targeted deletion of PAD4 in neutrophils or pharmacologic inhibition of PAD4 with JBI-589 reduced both primary tumor growth and lung metastases and substantially enhanced the effect of immune checkpoint inhibitors. Taken together, these results suggest a therapeutic potential of targeting PAD4 in cancer. SIGNIFICANCE: PAD4 regulates tumor progression by promoting neutrophil migration and can be targeted with a small molecule inhibitor to suppress tumor growth and metastasis and increase efficacy of immune checkpoint blockade therapy.


Assuntos
Armadilhas Extracelulares , Neoplasias Pulmonares , Animais , Modelos Animais de Doenças , Armadilhas Extracelulares/metabolismo , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares/patologia , Camundongos , Neutrófilos , Proteína-Arginina Desiminase do Tipo 4 , Receptores de Quimiocinas/metabolismo
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