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1.
Eur J Immunol ; 54(6): e2350878, 2024 Jun.
Article de Anglais | MEDLINE | ID: mdl-38581345

RÉSUMÉ

Tumor-associated macrophages (TAM) are abundant in several tumor types and usually correlate with poor prognosis. Previously, we demonstrated that anti-inflammatory macrophages (M2) inhibit NK cell effector functions. Here, we explored the impact of TAM on NK cells in the context of clear-cell renal cell carcinoma (ccRCC). Bioinformatics analysis revealed that an exhausted NK cell signature strongly correlated with an M2 signature. Analysis of TAM from human ccRCC samples confirmed that they exhibited an M2-skewed phenotype and inhibited IFN-γ production by NK cells. Moreover, human M0 macrophages cultured with conditioned media from ccRCC cell lines generated macrophages with an M2-skewed phenotype (TAM-like), which alike TAM, displayed suppressive activity on NK cells. Moreover, TAM depletion in the mouse Renca ccRCC model resulted in delayed tumor growth and reduced volume, accompanied by an increased frequency of IFN-γ-producing tumor-infiltrating NK cells that displayed heightened expression of T-bet and NKG2D and reduced expression of the exhaustion-associated co-inhibitory molecules PD-1 and TIM-3. Therefore, in ccRCC, the tumor microenvironment polarizes TAM toward an immunosuppressive profile that promotes tumor-infiltrating NK cell dysfunction, contributing to tumor progression. In addition, immunotherapy strategies targeting TAM may result in NK cell reinvigoration, thereby counteracting tumor progression.


Sujet(s)
Néphrocarcinome , Interféron gamma , Tumeurs du rein , Cellules tueuses naturelles , Macrophages associés aux tumeurs , Cellules tueuses naturelles/immunologie , Néphrocarcinome/immunologie , Néphrocarcinome/anatomopathologie , Interféron gamma/métabolisme , Interféron gamma/immunologie , Humains , Animaux , Souris , Tumeurs du rein/immunologie , Tumeurs du rein/anatomopathologie , Macrophages associés aux tumeurs/immunologie , Macrophages associés aux tumeurs/métabolisme , Évolution de la maladie , Lignée cellulaire tumorale , Microenvironnement tumoral/immunologie , Sous-famille K des récepteurs de cellules NK de type lectine/métabolisme , Récepteur cellulaire-2 du virus de l'hépatite A/métabolisme , Récepteur cellulaire-2 du virus de l'hépatite A/immunologie , Récepteur-1 de mort cellulaire programmée/métabolisme
2.
Front Endocrinol (Lausanne) ; 14: 1144016, 2023.
Article de Anglais | MEDLINE | ID: mdl-37181035

RÉSUMÉ

Background: Stromal adipocytes and tumor breast epithelial cells undergo a mutual metabolic adaptation within tumor microenvironment. Therefore, browning and lipolysis occur in cancer associated adipocytes (CAA). However, the paracrine effects of CAA on lipid metabolism and microenvironment remodeling remain poorly understood. Methods: To analyze these changes, we evaluated the effects of factors in conditioned media (CM) derived from explants of human breast adipose tissue from tumor (hATT) or normal (hATN) on morphology, degree of browning, the levels of adiposity, maturity, and lipolytic-related markers in 3T3-L1 white adipocytes by Western blot, indirect immunofluorescence and lipolytic assay. We analyzed subcellular localization of UCP1, perilipin 1 (Plin1), HSL and ATGL in adipocytes incubated with different CM by indirect immunofluorescence. Additionally, we evaluated changes in adipocyte intracellular signal pathways. Results: We found that adipocytes incubated with hATT-CM displayed characteristics that morphologically resembled beige/brown adipocytes with smaller cell size and higher number of small and micro lipid droplets (LDs), with less triglyceride content. Both, hATT-CM and hATN-CM, increased Pref-1, C/EBPß LIP/LAP ratio, PPARγ, and caveolin 1 expression in white adipocytes. UCP1, PGC1α and TOMM20 increased only in adipocytes that were treated with hATT-CM. Also, hATT-CM increased the levels of Plin1 and HSL, while decreased ATGL. hATT-CM modified the subcellular localization of the lipolytic markers, favoring their relative content around micro-LDs and induced Plin1 segregation. Furthermore, the levels of p-HSL, p-ERK and p-AKT increased in white adipocytes after incubation with hATT-CM. Conclusions: In summary, these findings allow us to conclude that adipocytes attached to the tumor could induce white adipocyte browning and increase lipolysis as a means for endocrine/paracrine signaling. Thus, adipocytes from the tumor microenvironment exhibit an activated phenotype that could have been induced not only by secreted soluble factors from tumor cells but also by paracrine action from other adipocytes present in this microenvironment, suggesting a "domino effect".


Sujet(s)
Adipocytes blancs , Lipolyse , Humains , Adipocytes blancs/métabolisme , Tissu adipeux/métabolisme , Métabolisme lipidique , Adipocytes bruns/métabolisme , Périlipine-1
3.
Front Immunol ; 12: 745939, 2021.
Article de Anglais | MEDLINE | ID: mdl-34616407

RÉSUMÉ

Natural Killer (NK) cells play a key role in cancer immunosurveillance. However, NK cells from cancer patients display an altered phenotype and impaired effector functions. In addition, evidence of a regulatory role for NK cells is emerging in diverse models of viral infection, transplantation, and autoimmunity. Here, we analyzed clear cell renal cell carcinoma (ccRCC) datasets from The Cancer Genome Atlas (TCGA) and observed that a higher expression of NK cell signature genes is associated with reduced survival. Analysis of fresh tumor samples from ccRCC patients unraveled the presence of a high frequency of tumor-infiltrating PD-L1+ NK cells, suggesting that these NK cells might exhibit immunoregulatory functions. In vitro, PD-L1 expression was induced on NK cells from healthy donors (HD) upon direct tumor cell recognition through NKG2D and was further up-regulated by monocyte-derived IL-18. Moreover, in vitro generated PD-L1hi NK cells displayed an activated phenotype and enhanced effector functions compared to PD-L1- NK cells, but simultaneously, they directly inhibited CD8+ T cell proliferation in a PD-L1-dependent manner. Our results suggest that tumors might drive the development of PD-L1-expressing NK cells that acquire immunoregulatory functions in humans. Hence, rational manipulation of these regulatory cells emerges as a possibility that may lead to improved anti-tumor immunity in cancer patients.


Sujet(s)
Antigène CD274/biosynthèse , Lymphocytes T CD8+/cytologie , Néphrocarcinome/immunologie , Tumeurs du rein/immunologie , Cellules tueuses naturelles/métabolisme , Néphrocarcinome/génétique , Néphrocarcinome/métabolisme , Néphrocarcinome/mortalité , Lignée cellulaire tumorale , Prolifération cellulaire , Cellules cultivées , Jeux de données comme sujet , Survie sans rechute , Expression des gènes , Humains , Interféron gamma/pharmacologie , Interleukine-18/pharmacologie , Cellules K562 , Estimation de Kaplan-Meier , Tumeurs du rein/génétique , Tumeurs du rein/métabolisme , Tumeurs du rein/mortalité , Monitorage immunologique , Monocytes/métabolisme , Protéines recombinantes/pharmacologie , Régulation positive
4.
Oncol Rep ; 45(1): 317-328, 2021 01.
Article de Anglais | MEDLINE | ID: mdl-33416183

RÉSUMÉ

Adipocytes are the main stromal cells in the mammary microenvironment, and crosstalk between adipocytes and breast cancer cells may play a critical and important role in cancer maintenance and progression. Tumor­induced differentiation to beige/brown adipose tissue is an important contribution to the hypermetabolic state of breast cancer. However, the effect of epithelial cell­beige adipocyte communication on tumor progression remains unclear. To contribute to the understanding of this phenomenon, we characterized components present in conditioned media (CM) from beige adipocytes (BAs) or white adipocytes (WAs), and evaluated the effects of BA­ and WA­CM on both adhesion and migration of tumor (LM3, 4T1 and MC4­L1) and non­tumor (NMuMG) mouse mammary epithelial cell lines. Additionally, we analyzed the expression of ObR, CD44, vimentin, MMP­9, MCT1 and LDH in tumor and non­tumor mouse mammary epithelial cell lines incubated with BA­CM, WA­CM or Ctrol­CM (control conditioned media). 3T3­L1 preadipocytes differentiated into beige adipocytes upon PPARγ activation (rosiglitazone) displaying characteristics that morphologically resembled brown/beige adipocytes. Levels of UCP1, CIDEA, GLUT4, leptin, MCT4 and FABP4 were increased, while adiponectin, caveolin 1 and perilipin 1 levels were decreased in BAs with respect to WAs. Tumor cell lines revealed lower cell adhesion and increased cell migration after incubation with BA­ and WA­CM vs. Ctrol­CM. ObR and MMP­9 in MC4­L1 cells were significantly increased after incubation with BA­CM vs. WA­ and Ctrol­CM. In addition, MC4­L1 and LM3 cells significantly increased their migration in the presence of BAs, suggesting that new signals originating from the crosstalk between BAs and tumor cells, could be responsible for this change. Our results indicate that beige adipocytes are able to regulate the behavior of both tumor and non­tumor mouse mammary epithelial cells, favoring tumor progression.


Sujet(s)
Adipocytes beiges/métabolisme , Tumeurs du sein/anatomopathologie , Tumeurs expérimentales de la mamelle/anatomopathologie , Cellules 3T3-L1 , Adipocytes beiges/effets des médicaments et des substances chimiques , Adipocytes blancs/effets des médicaments et des substances chimiques , Adipocytes blancs/métabolisme , Animaux , Adhérence cellulaire/effets des médicaments et des substances chimiques , Différenciation cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Mouvement cellulaire/effets des médicaments et des substances chimiques , Milieux de culture conditionnés/métabolisme , Évolution de la maladie , Femelle , Humains , Glandes mammaires animales , Souris , Récepteur PPAR gamma/agonistes , Récepteur PPAR gamma/métabolisme , Rosiglitazone/pharmacologie , Microenvironnement tumoral/effets des médicaments et des substances chimiques
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