Dataset Information

BAFF Attenuates Immunosuppressive Monocytes in the Melanoma Tumor Microenvironment.

ABSTRACT: Emerging evidence indicates B-cell activating factor (BAFF, Tnfsf13b) to be an important cytokine for antitumor immunity. In this study, we generated a BAFF-overexpressing B16.F10 melanoma cell model and found that BAFF-expressing tumors grow more slowly in vivo than control tumors. The tumor microenvironment (TME) of BAFF-overexpressing tumors had decreased myeloid infiltrates with lower PD-L1 expression. Monocyte depletion and anti-PD-L1 antibody treatment confirmed the functional importance of monocytes for the phenotype of BAFF-mediated tumor growth delay. RNA sequencing analysis confirmed that monocytes isolated from BAFF-overexpressing tumors were characterized by a less exhaustive phenotype and were enriched for in genes involved in activating adaptive immune responses and NF-κB signaling. Evaluation of patients with late-stage metastatic melanoma treated with inhibitors of the PD-1/PD-L1 axis demonstrated a stratification of patients with high and low BAFF plasma levels. Patients with high BAFF levels experienced lower responses to anti-PD-1 immunotherapies. In summary, these results show that BAFF, through its effect on tumor-infiltrating monocytes, not only impacts primary tumor growth but can serve as a biomarker to predict response to anti-PD-1 immunotherapy in advanced disease. SIGNIFICANCE: The BAFF cytokine regulates monocytes in the melanoma microenvironment to suppress tumor growth, highlighting the importance of BAFF in antitumor immunity.

SUBMITTER: Liu W

PROVIDER: S-EPMC9397630 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

BAFF Attenuates Immunosuppressive Monocytes in the Melanoma Tumor Microenvironment.

Liu Wei W Stachura Paweł P Xu Haifeng C HC Váraljai Renáta R Shinde Prashant P Ganesh Nikkitha Umesh NU Mack Matthias M Van Lierop Anke A Huang Anfei A Sundaram Balamurugan B Lang Karl S KS Picard Daniel D Fischer Ute U Remke Marc M Homey Bernhard B Roesch Alexander A Häussinger Dieter D Lang Philipp A PA Borkhardt Arndt A Pandyra Aleksandra A AA

Cancer research 20211122 2

Emerging evidence indicates B-cell activating factor (BAFF, <i>Tnfsf13b</i>) to be an important cytokine for antitumor immunity. In this study, we generated a BAFF-overexpressing B16.F10 melanoma cell model and found that BAFF-expressing tumors grow more slowly <i>in vivo</i> than control tumors. The tumor microenvironment (TME) of BAFF-overexpressing tumors had decreased myeloid infiltrates with lower PD-L1 expression. Monocyte depletion and anti-PD-L1 antibody treatment confirmed the functiona ...[more]

PMID: 34810198

Similar Datasets

Project description:BackgroundConsidering melanoma is the deadliest malignancy among dermatoma and presently lacks effective therapies, there is an urgent need to investigate the potential mechanisms underlying melanoma metastasis and determine prospective therapeutic targets for precise treatment of melanoma.MethodHub genes in melanoma metastasis were identified by analyzing RNA-seq data (mRNA, miRNA, and lncRNA) obtained from TCGA database. Then the identified hub genes were validated in human tissues with qRT-PCR, followed by survival analysis. Competing endogenous RNAs of the hub genes were defined to clarify potential molecular mechanism of melanoma progression. Then central gene-related signaling pathways were analyzed, followed by immune cell abundance analysis in tumor microenvironment with CYTERSORTx.ResultA tetrad of IL2RA, IL2RG, IFNG, and IL7R genes were determined as hub genes and verified by qRT-PCR, which were significantly associated with unfavorable prognosis in melanoma. LINC02446, LINC01857, and LINC02384 may act as competing endogenous lncRNAs of IL2RA and IL7R through absorbing their shared miR.891a.5p and miR.203b.3p. JAK-STAT signaling pathway identified as the most relevant pathway in melanoma metastasis, as well as a wealthy of genes including TNFRSF 13B, TNFRSF17, TNFRSF9, TNFRSF8, TNFRSF13C, TNFRSF11B, LAG3, NRP1, ENTPD1, NT5E, CCL21, and CCR7, may induce tumor autoimmune suppression through enhancing regulatory T-cell abundance and performance in the tumor microenvironment. And regulatory T-cell proportion was indeed critically elevated in metastatic melanoma relative to primary melanoma, as well as in highly expressed IL2RA, IL2RG, IL7R, and IFNG group than their respective counterparts.ConclusionElevated IL2RA, IL2RG, IL7R, and IFNG expression may play a central role in promoting melanoma metastasis through up regulation of intratumoral regulatory T-cell proportion mainly by activation of JAK-STAT signaling pathway. LINC02446, LINC01857, and LINC02384 may stimulate melanoma progression by reducing tumor-protecting miR.891a.5p and miR.203b.3p. A number of identified molecules including TNFRSF13B, LAG3, NRP1, ENTPD1, NT5E, CCL21, and CCR7 can serve as future therapeutic targets in melanoma treatment.

Project description:BackgroundMolecular mechanisms underlying inflammation-associated breast tumor growth are poorly studied. S100A7, a pro-inflammatory molecule has been shown to enhance breast cancer growth and metastasis. However, the S100A7-mediated molecular mechanisms in enhancing tumor growth and metastasis are unclear.MethodsHuman breast cancer tissue and plasma samples were used to analyze the expression of S100A7, cPLA2, and PGE2. S100A7-overexpressing or downregulated human metastatic breast cancer cells were used to evaluate the S100A7-mediated downstream signaling mechanisms. Bi-transgenic mS100a7a15 overexpression, TNBC C3 (1)/Tag transgenic, and humanized patient-derived xenograft mouse models and cPLA2 inhibitor (AACOCF3) were used to investigate the role of S100A7/cPLA2/PGE2 signaling in tumor growth and metastasis. Additionally, CODEX, a highly advanced multiplexed imaging was employed to delineate the effects of S100A7/cPLA2 inhibition on the recruitment of various immune cells.ResultsIn this study, we found that S100A7 and cPLA2 are highly expressed and correlate with decreased overall survival in breast cancer patients. Further mechanistic studies revealed that S100A7/RAGE signaling promotes the expression of cPLA2 to mediate its oncogenic effects. Pharmacological inhibition of cPLA2 suppressed S100A7-mediated tumor growth and metastasis in multiple pre-clinical models including transgenic and humanized patient-derived xenograft (PDX) mouse models. The attenuation of cPLA2 signaling reduced S100A7-mediated recruitment of immune-suppressive myeloid cells in the tumor microenvironment (TME). Interestingly, we discovered that the S100A7/cPLA2 axis enhances the immunosuppressive microenvironment by increasing prostaglandin E2 (PGE2). Furthermore, CO-Detection by indEXing (CODEX) imaging-based analyses revealed that cPLA2 inhibition increased the infiltration of activated and proliferating CD4+ and CD8+ T cells in the TME. In addition, CD163+ tumor associated-macrophages were positively associated with S100A7 and cPLA2 expression in malignant breast cancer patients.ConclusionsOur study provides new mechanistic insights on the cross-talk between S100A7/cPLA2 in enhancing breast tumor growth and metastasis by generating an immunosuppressive TME that inhibits the infiltration of cytotoxic T cells. Furthermore, our studies indicate that S100A7/cPLA2 could be used as novel prognostic marker and cPLA2 inhibitors as promising drugs against S100A7-overexpressing aggressive breast cancer.

Project description:The dynamic composition of the tumor microenvironment (TME) can markedly alter the response to targeted therapies for colorectal cancer. Cancer-associated fibroblasts (CAF) are major components of TMEs that can direct and induce infiltration of immunosuppressive cells through secreted cytokines such as CXCL12. Ketogenic diets (KD) can inhibit tumor growth and enhance the anticancer effects of immune checkpoint blockade. However, the role of ketogenesis on the immunosuppressive TME is not known. Here, we show that decreased ketogenesis is a signature of colorectal cancer and that an increase in ketogenesis using a KD decreases CXCL12 production in tumors, serum, liver, and lungs. Moreover, increasing ketogenesis by overexpression of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) or treatment with the ketone body β-hydroxybutyrate markedly decreased expression of KLF5, which binds the CXCL12 promoter and induces CXCL12 expression in CAFs. KD decreased intratumoral accumulation of immunosuppressive cells, increased infiltration of natural killer and cytotoxic T cells, and enhanced the anticancer effects of PD-1 blockade in murine-derived colorectal cancer. Furthermore, increasing ketogenesis inhibited colorectal cancer migration, invasion, and metastasis in vitro and in vivo. Overall, ketogenesis is downregulated in the colorectal cancer TME, and increased ketogenesis represses KLF5-dependent CXCL12 expression to improve the immunosuppressive TME, which leads to the enhanced efficacy of immunotherapy and reduced metastasis. Importantly, this work demonstrates that downregulation of de novo ketogenesis in the TME is a critical step in colorectal cancer progression.SignificanceThis study identifies ketogenesis as a critical regulator of the tumor microenvironment in colorectal cancer and suggests the potential for ketogenic diets as a metabolic strategy to overcome immunosuppression and prolong survival. See related commentary by Montrose and Galluzzi, p. 1464.

Project description:BackgroundAlthough melanoma is generally regarded as an immunogenic cancer that will respond to immune checkpoint inhibitors (ICIs), melanomas with CCND1 amplification respond poorly to these therapies. Further understanding how CCND1 amplification impacts the effectiveness of ICI therapy is important for the design of future clinical trials.MethodsWe used data from tumor samples taken from Chinese patients with melanoma analyzed at the Geneplus Institute (n=302), as well as data from the Cancer Genome Atlas (TCGA) database (n=367) and the Memorial Sloan Kettering Cancer Center (MSKCC) database (n=350) to estimate the prevalence of CCND1 amplification in melanoma, interrogate the relationship between CCND1 amplification and survival in patients with melanoma, and explore the molecular mechanisms of CCND1 amplification. We also established a murine model of melanoma harboring CCND1 amplification and utilized RNA-seq to verify the findings from human tissue samples.ResultsData from all three sources revealed a low frequency of CCND1 amplification co-occurring with BRAF V600, NRAS, NF1, and KIT mutations. Data from TCGA did not show a statistically significant correlation between CCND1 amplification and prognosis, irrespective of ICI use. In contrast, the MSKCC cohort showed that CCND1 amplification was an unfavorable prognostic factor for patients with melanoma, especially for patients who received ICIs and had a high tumor mutation burden (TMB). The TCGA data showed that CCND1 amplification was associated with a higher proportion of immunosuppressive cells (Treg cells and M2 macrophages) and a lower proportion of immune boosting cells (follicular helper T cells naïve B cells, CD8+ T cells). Murine models supported the association between a suppressive immune microenvironment and CCND1 amplification; tumors with CCND1 amplification had reduced mRNA expression of CD8, Gzm, B2m and Tap1, significantly higher proportions of resting CD4 memory T cells and significantly lower proportions of plasma cells, CD8 T cells, and T follicular helper cells. Furthermore, a Gene Set Enrichment Analysis (GSEA) analysis of data from the TCGA database suggested that signaling pathways involved in oxidative phosphorylation, reactive oxygen species, adipogenesis, fatty acid metabolism, DNA repair, and Myc targets were differentially enriched in melanoma tumors with CCND1 amplification. Finally, we observed a notable reduction in levels of angiogenesis-related molecules (encoded by HIF1A, VEGFA, VEGFR1, FGF2, FGFR1, FGFR4, HGF, PDGFA, PDGFRA, ANGPT1, and ANGPT2) in a high CCND1 amplification group from the TCGA database.ConclusionsMelanoma with CCND1 amplification is an independent genomic subtype associated with a poor prognosis, an immunosuppressive TME, activated oxidative and lipid metabolism, and down-regulated angiogenesis. Therefore, avoiding ICIs and antiangiogenic agents, while employing CDK4/6 inhibitors alone or in combination with ICIs, and targeting oxidative and lipid metabolism pathways, may be effective therapeutic strategies for melanoma patients harboring CCND1 amplification.

Dataset Information

BAFF Attenuates Immunosuppressive Monocytes in the Melanoma Tumor Microenvironment.

Publications

BAFF Attenuates Immunosuppressive Monocytes in the Melanoma Tumor Microenvironment.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets