Inflammation affects tumor immune surveillance and resistance to therapy. Here, we show that production of IL1β in primary breast cancer tumors is linked with advanced disease and originates from tumor-infiltrating CD11c myeloid cells. IL1β production is triggered by cancer cell membrane-derived TGFβ. Neutralizing TGFβ or IL1 receptor prevents breast cancer progression in humanized mouse model. Patients with metastatic HER2 breast cancer display a transcriptional signature of inflammation in the blood leukocytes, which is attenuated after IL1 blockade. When present in primary breast cancer tumors, this signature discriminates patients with poor clinical outcomes in two independent public datasets (TCGA and METABRIC). IL1β orchestrates tumor-promoting inflammation in breast cancer and can be targeted in patients using an IL1 receptor antagonist. .

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BackgroundRecent large-scale cancer sequencing studies have discovered many novel cancer driver genes (CDGs) in human cancers. Some studies also suggest that CDG mutations contribute to cancer-associated epigenomic and transcriptomic alterations across many cancer types. Here we aim to improve our understanding of the connections between CDG mutations and altered cancer cell epigenomes and transcriptomes on pan-cancer level and how these connections contribute to the known association between epigenome and transcriptome.MethodUsing multi-omics data including somatic mutation, DNA methylation, and gene expression data of 20 cancer types from The Cancer Genome Atlas (TCGA) project, we conducted a pan-cancer analysis to identify CDGs, when mutated, have strong associations with genome-wide methylation or expression changes across cancer types, which we refer as methylation driver genes (MDGs) or expression driver genes (EDGs), respectively.ResultsWe identified 32 MDGs, among which, eight are known chromatin modification or remodeling genes. Many of the remaining 24 MDGs are connected to chromatin regulators through either regulating their transcription or physically interacting with them as potential co-factors. We identified 29 EDGs, 26 of which are also MDGs. Further investigation on target genes’ promoters methylation and expression alteration patterns of these 26 overlapping driver genes shows that hyper-methylation of target genes’ promoters are significantly associated with down-regulation of the same target genes and hypo-methylation of target genes’ promoters are significantly associated with up-regulation of the same target genes.ConclusionThis finding suggests a pivotal role for genetically driven changes in chromatin remodeling in shaping DNA methylation and gene expression patterns during tumor development.Electronic supplementary materialThe online version of this article (10.1186/s12920-018-0425-z) contains supplementary material, which is available to authorized users.

Metastasis of melanoma significantly worsens prognosis; thus, therapeutic interventions that prevent metastasis could improve patient outcomes. Here, we show using humanized mice that colonization of distant visceral organs with melanoma is dependent upon a human CD33+CD11b+CD117+ progenitor cell subset comprising <4% of the human CD45+ leukocytes. Metastatic tumor-infiltrating CD33+ cells from patients and humanized (h)NSG-SGM3 mice showed converging transcriptional profiles. Single-cell RNA-seq analysis identified a gene signature of a KIT/CD117–expressing CD33+ subset that correlated with decreased overall survival in a TCGA melanoma cohort. Thus, human CD33+CD11b+CD117+ myeloid cells represent a novel candidate biomarker as well as a therapeutic target for metastatic melanoma.

Women with triple-negative breast cancer (TNBC) have an increased pathologic complete response rate (pCR; residual disease after neoadjuvant chemotherapy) as compared to women with non-TNBC, and those with pCR have a 90% disease-free survival. However, women with TNBC who do not achieve a pCR have an increased risk of recurrence, decreased overall survival, and post-recurrence survival as compared to women with non-TNBC who do not achieve a pCR. A high priority for clinical research is therefore to increase the pCR rate in breast and axilla with preoperative therapy, as therapeutic options for patients who do not have a pCR are limited. Immunotherapy is an attractive strategy as human BCs can be immunogenic and enhancing the immune effector function may augment the cytotoxic effects of standard therapies. Immunity against tumor antigens can be boosted in cancer patients by vaccination with ex vivo-generated tumor antigen-loaded DCs. Here, we report the extended analysis of a clinical trial on 10 TNBC pts assessing the feasibility of combining cyclin B1/WT1/CEF (antigen)-loaded DC vaccination with preoperative chemotherapy in patients with locally advanced TNBC. Combination of preoperative chemotherapy and intratumoral and subcutaneous autologous DC vaccination led to 70% of combined rate of pCR and residual cancer burden 1 (RCB1). To assess expansion of antigen-specific T cell responses, IFN-g-ELISpot was carried out with PBMCs from baseline (BL) and several time points during vaccine treatment that were cultured with control peptides or with peptide libraries covering vaccine antigens. The expansion of antigen-specific immune responses could be detected at various time points post treatment. Transciptional profiling on blood (Nanostring) and tumors (RNAseq) revealed profound changes in immune transcription signatures. T cell and DC signatures in blood and T cell, inflammation, cytotoxic and cell cycle signatures in pre-chemotherapy breast cancer biopsies were linked with pathological responses in definitive surgery specimens. Taken together, differential gene and immunologic signatures of the pre-treatment breast cancer biopsies distinguish pts who have a pCR vs no pCR and can identify potential therapeutic targets for pts with TNBC. Citation Format: Te-Chia Wu, Joyce O’Shaughnessy, Lee K. Roberts, Jennifer L. Smith, Susan B. Burkeholder, Jennifer Finholt, Jessica Tarnowski, Tuoc Dao, Jeffrey Lamont, Sandra M. Zurawski, Phuong Nguyen, Yuanyuan Wang, Kyung In Kim, Derek Blankenship, Jacob Turner, Xuan Wang, Florentina Marches, Maren K. Levin, Michael Grant, Gerard Zurawski, Virginia Pascual, Jacques Banchereau, Karolina Palucka. Immune and transcriptional signatures of dendritic cell (DC) vaccination combined with chemotherapy in locally advanced, triple-negative breast cancer (TNBC) patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-04-10.

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<p>Cytokines screening from breast tumor tissue</p>

<p>Sample information of invasive breast carcinoma dataset in TCGA and METABRIC</p>