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P38 blockade reverses the immune suppressive microenvironment in metastatic breast cancer

ABSTRACT: The study investigated the role of p38α in regulating the outcome of the immune-tumor interaction in metastatic breast cancer. Single-cell transcriptomic analysis of the immune-TME showed that pharmacological p38 inhibition (p38i) or tumor-specific inactivation of p38α by CRISPR/Cas9 (p38KO) resulted in a less exhausted and more activated CD8+ T cell phenotype. Moreover, the myeloid cells in the TME exhibited reduced expression of immune-suppressive factors and chemotactic receptors. Overall, this study highlights a previously unrecognized p38α-driven pathway that promotes an immune suppressive TME and that therapeutic blockade of p38α has important implications for improving antitumor immunity and patient outcomes.

ORGANISM(S): Mus musculus

PROVIDER: GSE282734 | GEO | 2025/11/23

REPOSITORIES: GEO

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p38 blockade reverses the immune suppressive microenvironment in metastatic breast cancer

Project description:p38 blockade reverses the immune suppressive microenvironment in metastatic breast cancer

| PRJNA1190093 | ENA

Sex-specific control of CNS autoimmunity by p38 MAPK signaling in myeloid cells

Project description:Objective: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), characterized by a global increasing incidence driven by relapsing-remitting disease in females. p38 MAP kinase (MAPK) has been described as a key regulator of inflammatory responses in autoimmunity, but its role in the sexual dimorphism in MS or MS models remains unexplored. Methods: Toward this end, we used experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS, combined with pharmacologic and genetic inhibition of p38 MAPK activity and transcriptomic analyses. Results: Pharmacologic inhibition of p38 MAPK selectively ameliorated EAE in female mice. Conditional deletion studies demonstrated that p38α signaling in macrophages/myeloid cells, but not T cells or dendritic cells, recapitulated this sexual dimorphism. Analysis of CNS inflammatory infiltrates showed that female, but not male mice lacking p38α in myeloid cells exhibited reduced immune cell activation compared with controls, while peripheral T cell priming was unaffected in both sexes. Transcriptomic analyses of myeloid cells revealed differences in p38α-controlled transcripts comprising female- and male-specific gene modules, with greater p38α dependence of pro-inflammatory gene expression in females. Interpretation: Our findings demonstrate a key role for p38α in myeloid cells in CNS autoimmunity and uncover important molecular mechanisms underlying sex differences in disease pathogenesis. Taken together, our results suggest that the p38 MAPK signaling pathway represents a novel target for much needed disease modifying therapies for MS

2013-10-29 | GSE51707 | GEO

p38 MAPK overexpression in heart in vivo.

Project description:Mitogen-activated protein kinases (MAPKs) regulate cardiomyocyte growth and apoptosis in response to extracellular stimulation, but the downstream effectors that mediate their pathophysiological effects remain poorly understood. We determined the targets and role of p38 MAPK in the heart in vivo by using local adenovirus-mediated gene transfer of constitutively active upstream kinase mitogen-activated protein kinase kinase 3b (MKK3bE) and wild-type p38α in rats. DNA microarray analysis of animals with cardiac-specific overexpression of p38 MAPK revealed that 264 genes were upregulated more than 2-fold including multiple genes controlling cell division, cell signaling, inflammation, adhesion and transcription. Several previously unknown p38 target genes were found. Using gel mobility shift assays we identified several cardiac transcription factors that were directly activated by p38 MAPK. Finally, we determined the functional significance of the altered cardiac gene expression profile by histological analysis and echocardiographic measurements, which indicated that p38 MAPK overexpression induced gene expression results in cell proliferation, myocardial inflammation and fibrosis. In conclusion, we defined the novel target genes and transcription factors as well as the functional effects of p38 MAPK in the heart. Expression profiling of p38 MAPK overexpression identified cell cycle regulatory and inflammatory genes critical for pathological processes in the adult heart. Keywords: Gene transfer

2006-12-19 | GSE3866 | GEO

Host-derived Interleukin 1α induces immune suppressive tumor microenvironment via regulation of monocyte-to-macrophage differentiation

Project description:Tumor-associated macrophages exhibit high heterogeneity and contribute to the establishment of an immune-suppressive tumor microenvironment (TME). Although numerous studies have demonstrated that extracellular factors promote macrophage proliferation and polarization, the regulatory mechanisms governing the differentiation process to generate phenotypically, and functionally diverse macrophage subpopulations remain largely unexplored. In this study, we examined the influence of interleukin 1α (IL-1α) on the development of an immune-suppressive TME using syngeneic transplantation murine models of breast cancer. Deletion of IL-1α led to the rejection of syngeneic tumor challenges. Single-cell sequencing analysis revealed that Cx3cr1+ macrophage cells were the primary sources of IL-1α in the TME. The absence of IL-1α reprogrammed the monocyte-to-macrophage differentiation process within the TME, characterized by a notable decrease in the subset of Cx3cr+ ductal-like macrophages and an increase in iNos-expressing stress-responsive cells. Comparative analysis of gene signatures in both human and mouse macrophage subsets suggested that IL-1α deficiency shifted macrophage polarization from M2 to M1 phenotypes, leading to enhanced cytotoxic T lymphocyte activity in the TME. Importantly, elevated levels of IL-1α in human cancers were associated with improved prognosis following immunotherapy. These findings underscore the pivotal role of IL-1α in shaping an immune-suppressive TME through the regulation of macrophage differentiation and activity, highlighting IL-1α as a potential target for breast cancer immunotherapy.

2024-12-31 | GSE264177 | GEO

Immune suppressive activity of myeloid-derived suppressor cells in cancer requires inactivation of the type I interferon pathway

Project description:Myeloid-derived suppressor cells (MDSC) are pathologically activated neutrophils and monocytes with potent immune suppressive activity. These cells play an important role in accelerating tumor progression and undermining the efficacy of anti-cancer therapies. The natural mechanisms limiting MDSC activity are not well understood. Here, we present evidence that type I interferons (IFN1) receptor signaling serves as a universal mechanism that restricts acquisition of suppressive activity by these cells. Downregulation of the IFNAR1 chain of this receptor was found in MDSC from cancer patients and mouse tumor models. The decrease in IFNAR1 depended on the activation of the p38 protein kinase and was required for activation of the immune suppressive phenotype. Whereas deletion of IFNAR1 was not sufficient to convert neutrophils and monocytes to MDSC, genetic stabilization of IFNAR1 in tumor bearing mice undermined suppressive activity of MDSC and had potent antitumor effect. Stabilizing IFNAR1 using inhibitor of p38 combined with the interferon induction therapy elicited a robust anti-tumor effect. Thus, negative regulatory mechanisms of MDSC function can be exploited therapeutically.

2021-02-15 | GSE166770 | GEO

Proximity assay of p38alpha MAPK reveals alternative splicing regulatory mechanism in cardiomyocyte.

Project description:The mitogen-activated protein kinase (MAPK) p38 signaling pathway is essential for normal heart function. However, p38 also contributes to heart failure pathogenesis by affecting heart contractility and cardiomyocyte survival. To unravel the complex cardiac role of p38, we report the interactome of p38α and p38γ, the two well expressed isoforms in the heart, obtained via an APEX proximity assay performed in cultured neonatal rat ventricular myocytes. The p38α and p38γ have distinct interactomes in cardiomyocytes for both studied states; basal and activated by an osmotic stress. Interestingly, the activated p38α interactome contains many spliceosome implicated RNA-binding proteins. The serine/arginine-rich splicing factor 3 (SRSF3) is of particular interest and its interaction with p38α was validated by co-immunoprecipitation. p38 is sufficient to partially relocate nuclear SRSF3 to cytoplasm. The alternative splicing function of SRSF3 is also modulated by the p38 pathway. Our findings reveal a novel set of proteins to investigate in order to decipher cardiac functions of the MAPK p38, as well as a specific regulation mechanism of SRSF3 by p38 in cardiomyocytes.

2021-03-01 | PXD011089 | Pride

Effect of depletion of p38α and p38beta on gene expression in primary effector CD8+ T cells

Project description:p38 MAPK is activated during CD8+ T cell primary response. p38 activation promotes effector CD8+ T cell terminal differentiation but represses MPEC formation. p38α/beta deficient mice possess a similar number of virus-specific effector CD8+ T cells as wildtype counterparts. Meanwhile p38α/beta deletion doesn’t influence the clearance of LCMV although it impairs the cytolytic activity of CD8+ T cells. Loss of p38α/beta significantly enhances IL-2-producing Tcm accumulation in mouse spleen with no impact on total memory CD8+ T cell numbers yet. And in line with this, more robust proliferation of memory CD8+ T cells in the secondary response and stronger antigen-specific killing ability in rechallenged mice are resulted from p38α/beta deficiency. These results establish a pivotal role for p38α/beta in skewing MPEC formation toward SLEC differentiation, as well as in suppressing Tcm formation, and thus affecting the recall response.

2023-08-01 | GSE239348 | GEO

Heyndrickxia coagulans P38

Project description:BACILLUS-COAGULANS-P38

| PRJNA218161 | ENA

Differential modulation of the phosphoproteome by the MAP Kinases isoforms p38α and p38β

Project description:The stress-activated p38 mitogen activated protein kinases (MAPK) mediate responses to osmotic shock, radiation, immune stimuli, inflammatory cues, and many other stresses. These kinases are activated rapidly, within seconds of stress induction, yet, their continuous activation, as commonly happens in inflammations and cancer, induce different signaling cascades than transient activation. This study aimed to follow the specific signaling cascades induced by two of these p38 MAPKs activated by strong and rapid stress, or by continuous (chronic) activations. The analysis was based on large-scale proteomics and phosphoproteomics analyses using SILAC labeling of mouse embryonic fibroblasts (MEF) deficient in each of these p38 kinases, expressing constitutively expressed wildtype p38α or p38β, or their intrinsically active variants. In addition, the effects of anisomycin, inducing strong and rapid stress response, were followed in wildtype MEF or in MEF knocked-out for these p38α or p38β. The signaling events, induced the each p38 during the chronic responses, indicated adaptations of the cells expressing the intrinsically active p38 mutants. The continuous activities of the individual p38 induced feedback loops that inactivated the other p38s. Furthermore, a number of new phosphorylation sites on proteins relevant to stress responses and cancer, such as p53 and p27, were revealed in this study.

2023-10-24 | PXD038389 | Pride

p38 alpha activates purine metabolism to initiate hematopoietic stem/progenitor cell cycling

Project description:Hematopoietic stem cells (HSCs) maintain quiescence by activating specific metabolic pathways, including glycolysis. However, how stress hematopoiesis, including bone marrow transplantation, induces metabolic changes in hematopoietic stem/progenitor cells (HSPCs) remains unclear. Here, we report a critical role for the p38MAPK family isoform p38α in initiating HSPC proliferation during stress hematopoiesis in mouse. We found that p38MAPK is immediately phosphorylated in HSPCs after hematological stress. p38α loss resulted in defective recovery from hematological stress and a delay in initiation of HSPC cycling. Bone marrow transplant altered levels of amino acids and purine-related metabolites in a p38α-dependent manner. Mechanistically, p38α signaling increases expression of inosine-5’-monophosphate dehydrogenase 2 in HSPCs after transplantation, an activity correlated with perturbed cell cycle progression in vitro and in vivo. Overall, we propose a novel mechanism governing HSPC cell cycle initiation via metabolic signaling in response to stress.

2016-04-20 | GSE80420 | GEO

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