Immunosurveillance constitutes the first step of cancer immunoediting in which developing malignant lesions are eliminated by anti-tumorigenic immune cells. However, the mechanisms by which neoplastic cells induce an immunosuppressive state to evade the immune response are still unclear. The transcription factor Stat3 has been implicated in breast carcinogenesis and tumor immunosuppression in advanced disease, but its involvement in early disease development has not been established. Here, we genetically ablated Stat3 in the tumor epithelia of the inducible PyVmT mammary tumor model and found that Stat3-deficient mice recapitulated the three phases of immunoediting: elimination, equilibrium, and escape. Pathological analyses revealed that Stat3-deficient mice initially formed hyperplastic and early adenoma-like lesions that later completely regressed, thereby preventing the emergence of mammary tumors in the majority of animals. Furthermore, tumor regression was correlated with massive immune infiltration into the Stat3-deficient lesions, leading to their elimination. In a minority of animals, focal, non-metastatic Stat3-deficient mammary tumors escaped immunosurveillance after a long latency or equilibrium period. Taken together, our findings suggest that tumor epithelial expression of Stat3 plays a critical role in promoting an immunosuppressive tumor microenvironment during breast tumor initiation and progression, and prompt further investigation of Stat3 inhibitory strategies that may reactivate the immunosurveillance program.
STAT3 Establishes an Immunosuppressive Microenvironment during the Early Stages of Breast Carcinogenesis to Promote Tumor Growth and Metastasis.
Age, Specimen part
View SamplesThe goal of this study is to compare tumor-infiltrating antigen presenting cell populations by global transcriptome profiling (RNA-seq) to help further delineate sub-populations of infiltrating myeloid cells in tumor. Methods: Four tumor antigen presenting cell populations were sorted from digested B78chOVA (melanoma variant) tumors in biological triplicate Results: RNA was extracted from the 4 groups (n=3 per group) and prepared for RNAseq. Sequencing yielded ~405 million reads with an average read depth of 33.7 million reads/sample. Reads were then aligned to the mouse genome (UCSC mm10) and those that mapped uniquely to known mRNAs were used to assess differential expression. Overall design: Examination of four tumor infiltrating myeliod populations
Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity.
No sample metadata fields
View SamplesIntratumoral stimulatory dendritic cells (SDCs) play an important role in locally restimulating cytotoxic T cells and driving immune responses against cancer. However, the mechanisms that control SDC numbers remain poorly understood. In human melanoma, SDC numbers correlated with intratumoral expression of the gene encoding the cytokine FLT3LG, and we subsequently found in mouse and human tumors that this cytokine was predominantly produced by lymphocytes, notably including natural killer (NK) cells. NK cells stably formed conjugates with SDCs in the mouse tumor microenvironment (TME) and genetic and cellular ablation of NK cells in mice demonstrated their importance in regulation of SDC numbers through production of Flt3L. Although anti-PD-1 “checkpoint” immunotherapy for cancer largely targets T cells, we found that NK cells correlated with protective SDCs in human cancers, with patient responsiveness to anti-PD-1 immunotherapy, and with better overall survival. Our studies reveal that innate immune SDCs and NK cells cluster together as the best prognostic tool for T cell directed immunotherapy and that these innate cells are necessary for enhanced T cell tumor responses, suggesting this axis for novel therapies. Overall design: This dataset is n=11 biologically independent metastatic melanoma samples from patient tumors. There is no control dataset.
A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments.
Subject
View SamplesPurpose: In our study, we identified a heterogeneity among bone marrow (BM) Ly6Chi monocytes, which can be subdivided the expression of CXCR4. In order to understand the development of BM monocytes, the goal of this experiment is to compare the transcriptome of these 2 BM Ly6Chi monocyte subsets to those of the common monocyte progenitor (cMoP) and Ly6Clo monocytes. Overall design: 4 BM monocyte subsets (cMoP, Ly6ChiCXCR4hi, Ly6ChiCXCR4lo and Ly6Clo) from 3 different mice were sorted using a BD Aria III. Total RNA was extracted, converted to cDNA and run through deep sequencing using Illumina HiSeq 2500
CXCR4 identifies transitional bone marrow premonocytes that replenish the mature monocyte pool for peripheral responses.
Age, Specimen part, Cell line, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Dynamic transcriptional events in embryonic stem cells mediated by the super elongation complex (SEC).
Specimen part, Cell line, Treatment
View SamplesPhysiologically relevant concentrations of retinoic acid are added to Mouse ES cells and a time course (0-72 hours) is examined with expression tiling arrays and RNA-seq to characterize the early dynamics of expression of coding and non-coding RNAs in and around the Hox clusters. Overall design: Gene expression is examined at various timepoints (0-72 hrs) after retinoic acid induced neuronal differentiation
Dynamic regulation of Nanog and stem cell-signaling pathways by Hoxa1 during early neuro-ectodermal differentiation of ES cells.
No sample metadata fields
View SamplesMurine ES cell gene expression before RA induction are used to compare gene expression for time-points of 2, 4, 6hrs post-induction.
Dynamic transcriptional events in embryonic stem cells mediated by the super elongation complex (SEC).
No sample metadata fields
View SamplesTranscriptional regulation of developmentally controlled genes is at the heart of differentiation and organogenesis. In this study, we have performed mRNA transcript abdundance analyses in human cells in response to serum activation signal by RNA-seq. Overall design: mRNA transcript abundance determined before and after serum activation signals using two biological replicates.
Dynamic transcriptional events in embryonic stem cells mediated by the super elongation complex (SEC).
No sample metadata fields
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Poised RNA polymerase II changes over developmental time and prepares genes for future expression.
Specimen part, Cell line, Treatment, Time
View SamplesMurine ES cell gene expression before RA induction are used to compare gene expression for time-points of 8, 12, 16, 24, 36, 48, 60 and 72 hours post-induction.
Poised RNA polymerase II changes over developmental time and prepares genes for future expression.
Cell line, Treatment, Time
View Samples