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Cell Rep ; 33(13): 108571, 2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33378668


Here, we report that functional heterogeneity of macrophages in cancer could be determined by the nature of their precursors: monocytes (Mons) and monocytic myeloid-derived suppressor cells (M-MDSCs). Macrophages that are differentiated from M-MDSCs, but not from Mons, are immune suppressive, with a genomic profile matching that of M-MDSCs. Immune-suppressive activity of M-MDSC-derived macrophages is dependent on the persistent expression of S100A9 protein in these cells. S100A9 also promotes M2 polarization of macrophages. Tissue-resident- and Mon-derived macrophages lack expression of this protein. S100A9-dependent immune-suppressive activity of macrophages involves transcription factor C/EBPß. The presence of S100A9-positive macrophages in tumor tissues is associated with shorter survival in patients with head and neck cancer and poor response to PD-1 antibody treatment in patients with metastatic melanoma. Thus, this study reveals the pathway of the development of immune-suppressive macrophages and suggests an approach to their selective targeting.

Clin Cancer Res ; 25(9): 2783-2794, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30765391


PURPOSE: BRAF and MEK inhibitors (BRAFi and MEKi) are actively used for the treatment of metastatic melanoma in patients with BRAFV600E mutation in their tumors. However, the development of resistance to BRAFi and MEKi remains a difficult clinical challenge with limited therapeutic options available to these patients. In this study, we investigated the mechanism and potential therapeutic utility of combination BRAFi and adoptive T-cell therapy (ACT) in melanoma resistant to BRAFi. EXPERIMENTAL DESIGN: Investigations were performed in vitro and in vivo with various human melanoma cell lines sensitive and resistant to BRAFi as well as patient-derived xenografts (PDX) derived from patients. In addition, samples were evaluated from patients on a clinical trial of BRAFi in combination with ACT. RESULTS: Herein we report that in human melanoma cell lines, senstitive and resistant to BRAFi and in PDX from patients who progressed on BRAFi and MEKi therapy, BRAFi caused transient upregulation of mannose-6-phosphate receptor (M6PR). This sensitized tumor cells to CTLs via uptake of granzyme B, a main component of the cytotoxic activity of CTLs. Treatment of mice bearing resistant tumors with BRAFi enhanced the antitumor effect of patients' TILs. A pilot clinical trial of 16 patients with metastatic melanoma who were treated with the BRAFi vemurafenib followed by therapy with TILs demonstrated a significant increase of M6PR expression on tumors during vemurafenib treatment. CONCLUSIONS: BRAF-targeted therapy sensitized resistant melanoma cells to CTLs, which opens new therapeutic opportunities for the treatment of patients with BRAF-resistant disease.See related commentary by Goff and Rosenberg, p. 2682.

Melanoma , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Animais , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Camundongos , Inibidores de Proteínas Quinases , Linfócitos T
Cancer ; 125(10): 1717-1725, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30633331


BACKGROUND: Women with breast cancer (BCa) experience heightened distress, which is related to greater inflammation and poorer outcomes. The s100 protein family facilitates the inflammatory response by regulating myeloid cell function through the binding of Toll-like receptor 4 and the receptor for advanced glycation end products (RAGE). The heterodimer s100A8/A9 RAGE ligand is associated with hastened tumor development and metastasis. Previously, a 10-week stress-management intervention using cognitive behavioral therapy (CBT) and relaxation training (RT) was associated with less leukocyte inflammatory gene expression in patients with BCa; however, its impact on s100A8/A9 was not examined. Because a 10-week intervention may be impractical during primary treatment for BCa, the authors developed briefer forms of CBT and RT and demonstrated their efficacy in reducing distress over 12 months of primary treatment. Here, the effects of these briefer interventions were tested effects on s100A8/A9 levels over the initial 12 months of BCa treatment. METHODS: Postsurgical patients with BCa (stage 0-IIIB) were randomized to a 5-week, group-based condition: CBT, RT, or health education control (HE). At baseline and at 12 months, women provided sera from which s100A8/A9 levels were determined using any enzyme-linked immunosorbent assay. RESULTS: Participants (mean age ± standard deviation, 54.81 ± 9.63 years) who were assigned to either CBT (n = 41) or RT (n = 38) had significant s100A8/A9 decreases over 12 months compared with those who were assigned to HE (n = 44; F[1,114]  = 4.500; P = .036) controlling for age, stage, time since surgery, and receipt of chemotherapy or radiation. Greater increases in stress-management skills from preintervention to postintervention predicted greater reductions in s100A8/A9 levels over 12 months (ß = -0.379; t[101]  = -4.056; P < .001). CONCLUSIONS: Brief, postsurgical, group-based stress management reduces RAGE-associated s100A8/A9 ligand levels during primary treatment for BCa.

Neoplasias da Mama/genética , Calgranulina A/metabolismo , Calgranulina B/metabolismo , Terapia Cognitivo-Comportamental/métodos , Terapia de Relaxamento/métodos , Estresse Psicológico/terapia , Idoso , Análise de Variância , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/psicologia , Neoplasias da Mama/cirurgia , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Mediadores da Inflamação/metabolismo , Pessoa de Meia-Idade , Valores de Referência , Estresse Psicológico/diagnóstico , Resultado do Tratamento
J Biol Chem ; 291(23): 12057-73, 2016 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-27022018


The receptor for advanced glycation end products (RAGE) is a multiligand transmembrane receptor that can undergo proteolysis at the cell surface to release a soluble ectodomain. Here we observed that ectodomain shedding of RAGE is critical for its role in regulating signaling and cellular function. Ectodomain shedding of both human and mouse RAGE was dependent on ADAM10 activity and induced with chemical activators of shedding (ionomycin, phorbol 12-myristate 13-acetate, and 4-aminophenylmercuric acetate) and endogenous stimuli (serum and RAGE ligands). Ectopic expression of the splice variant of RAGE (RAGE splice variant 4), which is resistant to ectodomain shedding, inhibited RAGE ligand dependent cell signaling, actin cytoskeleton reorganization, cell spreading, and cell migration. We found that blockade of RAGE ligand signaling with soluble RAGE or inhibitors of MAPK or PI3K blocked RAGE-dependent cell migration but did not affect RAGE splice variant 4 cell migration. We finally demonstrated that RAGE function is dependent on secretase activity as ADAM10 and γ-secretase inhibitors blocked RAGE ligand-mediated cell migration. Together, our data suggest that proteolysis of RAGE is critical to mediate signaling and cell function and may therefore emerge as a novel therapeutic target for RAGE-dependent disease states.

Movimento Celular/fisiologia , Fenômenos Fisiológicos Celulares/fisiologia , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais/fisiologia , Proteína ADAM10/metabolismo , Sequência de Aminoácidos , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Sítios de Ligação/genética , Western Blotting , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Fenômenos Fisiológicos Celulares/efeitos dos fármacos , Fenômenos Fisiológicos Celulares/genética , Células HEK293 , Humanos , Ionomicina/farmacologia , Metaloproteases/metabolismo , Camundongos , Mutação , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteólise/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/genética , Homologia de Sequência de Aminoácidos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Acetato de Tetradecanoilforbol/farmacologia