Journal Articles

Host tissue determinants of tumour immunity

Although common evolutionary principles drive the growth of cancer cells regardless of the tissue of origin, the microenvironment in which tumours arise substantially differs across various organ sites. Recent studies have established that, in addition to cell-intrinsic effects, tumour growth regulation also depends on local cues driven by tissue environmental factors. In this Review, we discuss how tissue-specific determinants might influence tumour development and argue that unravelling the tissue-specific contribution to tumour immunity should help the development of precise immunotherapeutic strategies for patients with cancer.

Author Info: (1) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. helene.salmon@curie.fr. Precision Immunology Institute and Tisch Cancer Institut

Author Info: (1) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. helene.salmon@curie.fr. Precision Immunology Institute and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. helene.salmon@curie.fr. INSERM U932, Institut Curie, Paris, France. helene.salmon@curie.fr. (2) Innate Pharma, Marseille, France. (3) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (4) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. miriam.merad@mssm.edu. Precision Immunology Institute and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. miriam.merad@mssm.edu.

Modulation of TAP-dependent antigen compartmentalization during human monocyte-to-DC differentiation

Dendritic cells (DCs) take up antigen in the periphery, migrate to secondary lymphoid organs, and present processed antigen fragments to adaptive immune cells and thus prime antigen-specific immunity. During local inflammation, recirculating monocytes are recruited from blood to the inflamed tissue, where they differentiate to macrophages and DCs. In this study, we found that monocytes showed high transporter associated with antigen processing (TAP)-dependent peptide compartmentalization and that after antigen pulsing, they were not able to efficiently stimulate antigen-specific T lymphocytes. Nevertheless, upon in vitro differentiation to monocyte-derived DCs, TAP-dependent peptide compartmentalization as well as surface major histocompatibility complex I turnover decreased and the cells efficiently restimulated T lymphocytes. Although TAP-dependent peptide compartmentalization decreased during DC differentiation, TAP expression levels increased. Furthermore, TAP relocated from early endosomes in monocytes to the endoplasmic reticulum (ER) and lysosomal compartments in DCs. Collectively, these data are compatible with the model that during monocyte-to-DC differentiation, the subcellular relocation of TAP and the regulation of its activity assure spatiotemporal separation of local antigen uptake and processing by monocytes and efficient T-lymphocyte stimulation by DCs.

Author Info: (1) Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Res

Author Info: (1) Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and Hannover Medical School, Hannover, Germany. (2) Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Frankfurt, Germany. (3) Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Frankfurt, Germany. (4) Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany. (5) Institute of Molecular Bacteriology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and Hannover Medical School, Hannover, Germany. Department of Molecular Bacteriology, Helmholtz Centre for Infection Research, Braunschweig, Germany. (6) Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and Hannover Medical School, Hannover, Germany. Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Frankfurt, Germany. (7) Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and Hannover Medical School, Hannover, Germany. (8) Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and Hannover Medical School, Hannover, Germany. (9) Biostatistics, Helmholtz Centre for Infection Research, Braunschweig, Germany. (10) Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (11) Leibniz Institute for Neurobiology, Magdeburg, Germany. (12) Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (13) Biostatistics, Helmholtz Centre for Infection Research, Braunschweig, Germany. Department of Computer Science, Ostfalia University of Applied Sciences, Wolfenbuttel, Germany. (14) Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany. (15) Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Frankfurt, Germany. Cluster of Excellence Frankfurt-Macromolecular Complexes, Goethe University Frankfurt, Frankfurt, Germany; and. (16) Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and Hannover Medical School, Hannover, Germany. Cluster of Excellence-Resolving Infection Susceptibility, Hannover Medical School, Hannover, Germany.

Genomic correlates of response to immune checkpoint blockade

Despite impressive durable responses, immune checkpoint inhibitors do not provide a long-term benefit to the majority of patients with cancer. Understanding genomic correlates of response and resistance to checkpoint blockade may enhance benefits for patients with cancer by elucidating biomarkers for patient stratification and resistance mechanisms for therapeutic targeting. Here we review emerging genomic markers of checkpoint blockade response, including those related to neoantigens, antigen presentation, DNA repair, and oncogenic pathways. Compelling evidence also points to a role for T cell functionality, checkpoint regulators, chromatin modifiers, and copy-number alterations in mediating selective response to immune checkpoint blockade. Ultimately, efforts to contextualize genomic correlates of response into the larger understanding of tumor immune biology will build a foundation for the development of novel biomarkers and therapies to overcome resistance to checkpoint blockade.

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (2) Department of Medical Oncology, Dana-

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Immunology, Harvard Medical School, Boston, MA, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Eliezerm_vanallen@dfci.harvard.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Eliezerm_vanallen@dfci.harvard.edu.

Cognate Interaction With CD4(+) T Cells Instructs Tumor-Associated Macrophages to Acquire M1-Like Phenotype

The immunosuppressive tumor microenvironment (TME) established by tumor cells, stromal cells and inhibitory immune cells counteracts the function of tumor reactive T cells. Tumor associated macrophages (TAMs) showing functional plasticity contribute to this process as so called M2-like macrophages can suppress the function of effector T cells and promote their differentiation into regulatory T cells (Tregs). Furthermore, tumor antigen specific CD4(+) T effector cells can essentially sustain anti-tumoral immune responses as shown for various tumor entities, thus suggesting that cognate interaction between tumor antigen-specific CD4(+) Th1 cells and TAMs might shift the intra-tumoral M1/M2 ratio toward M1. This study demonstrates repolarization of M2-like PECs upon MHC II-restricted interaction with tumor specific CD4(+) Th1 cells in vitro as shown by extensive gene and protein expression analyses. Moreover, adoptive transfer of OVA-specific OT-II cells into C57BL/6 mice bearing OVA expressing IA(b-/-) tumors resulted in increased accumulation of M1-like TAMs with enhanced M1 associated gene and protein expression profiles. Thus, this paper highlights a so far underestimated function of the CD4(+) Th1/TAM axis in re-conditioning the immunosuppressive tumor microenvironment.

Author Info: (1) GMP & T Cell Therapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany. Biosciences Faculty, University of Heidelberg, Heidelberg, Germany. Biopharmaceutical New

Author Info: (1) GMP & T Cell Therapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany. Biosciences Faculty, University of Heidelberg, Heidelberg, Germany. Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany. (2) GMP & T Cell Therapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany. Biosciences Faculty, University of Heidelberg, Heidelberg, Germany. Division of Virology, Innsbruck Medical University, Innsbruck, Austria. (3) GMP & T Cell Therapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany. (4) Integrated Research and Treatment Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany. (5) GMP & T Cell Therapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany. (6) GMP & T Cell Therapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Multi-omics profiling reveals distinct microenvironment characterization and suggests immune escape mechanisms of triple-negative breast cancer

PURPOSE: The tumor microenvironment has a profound impact on prognosis and immunotherapy. However, the landscape of the triple-negative breast cancer (TNBC) microenvironment has not been fully understood. EXPERIMENTAL DESIGN: Using the largest original multi-omics dataset of TNBC (n = 386), we conducted an extensive immunogenomic analysis to explore the heterogeneity and prognostic significance of the TNBC microenvironment. We further analyzed the potential immune escape mechanisms of TNBC. RESULTS: The TNBC microenvironment phenotypes were classified into three heterogeneous clusters: cluster 1, the "immune-desert" cluster, with low microenvironment cell infiltration; cluster 2, the "innate immune-inactivated" cluster, with resting innate immune cells and nonimmune stromal cells infiltration; and cluster 3, the "immune-inflamed" cluster, with abundant adaptive and innate immune cells infiltration. The clustering result was validated internally with pathological sections and externally with TCGA and METABRIC cohorts. The microenvironment clusters had significant prognostic efficacy. In terms of potential immune escape mechanisms, cluster 1 was characterized by an incapability to attract immune cells, and MYC amplification was correlated with low immune infiltration. In cluster 2, chemotaxis but inactivation of innate immunity and low tumor antigen burden might contribute to immune escape, and mutations in the PI3K-AKT pathway might be correlated with this effect. Cluster 3 featured high expression of immune checkpoint molecules. CONCLUSIONS: Our study represents a step towards personalized immunotherapy for TNBC patients. Immune checkpoint inhibitors might be effective for "immune-inflamed" cluster, and the transformation of "cold tumors" into "hot tumors" should be considered for "immune-desert" and "innate immune-inactivated" clusters.

Author Info: (1) Department of Breast Surgery, Fudan University Shanghai Cancer Center. (2) Department of Breast Surgery, Fudan University Shanghai Cancer Center. (3) Department of Breast Surge

Author Info: (1) Department of Breast Surgery, Fudan University Shanghai Cancer Center. (2) Department of Breast Surgery, Fudan University Shanghai Cancer Center. (3) Department of Breast Surgery, Fudan University Shanghai Cancer Center. (4) Department of Epidemiology, School of Public Health, Fudan University. (5) Chinese National Human Genome Center and Shanghai Industrial Technology Institute (SITI). (6) SARI center for Stem Cell and Nanomedicine, Chinese Academy of Sciences. (7) Department of Pathology, Fudan University Shanghai Cancer Center. (8) Department of Breast Surgery, Fudan University Shanghai Cancer Center. (9) Fudan University Shanghai Cancer Center, Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University. (10) Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences. (11) Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological sciences, Chinese Academy of Sciences. (12) Fudan University. (13) Department of Pathology, Fudan University Shanghai Cancer Center. (14) Department of Genetics, Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center and Shanghai Academy of Science and Technology. (15) breast surgery, Fudan Univeristy shanghai caner center. (16) Department of Breast Surgery, Fudan University. (17) Shanghai Cancer Center, Fudan University. (18) Medical Oncology, Institute Paoli-Calmettes. (19) Department of Breast Surgery, Fudan University Shanghai Cancer Center. (20) Breast Surgery, Fudan University Shanghai Cancer Center zhimin_shao@yeah.net.

The microbiome, cancer, and cancer therapy

With the advent of next-generation sequencing, we have an unprecedented ability to study tumor and host genomes as well as those of the vast array of microorganisms that exist within living organisms. Evidence now suggests that these microbes may confer susceptibility to certain cancers and may also influence response to therapeutics. A prime example of this is seen with immunotherapy, for which gut microbes have been implicated in influencing therapeutic responses in preclinical models and patient cohorts. However, these microbes may influence responses to other forms of therapy as well and may also affect treatment-associated toxicity. Based on these influences, there is growing interest in targeting these microbes in the treatment of cancer and other diseases. Yet complexities exist, and a deeper understanding of host-microbiome interactions is critical to realization of the full potential of such approaches. These concepts and the means through which such findings may be translated into the clinic will be discussed herein.

Author Info: (1) Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA. (3) Department o

Author Info: (1) Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA. (5) Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA. jwargo@mdanderson.org. Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, USA. jwargo@mdanderson.org.

Glioblastoma-Derived IL-6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth

PURPOSE: Upregulation of programmed death-ligand 1 (PD-L1) on circulating and tumor-infiltrating myeloid cells is a critical component of GBM-mediated immunosuppression that has been associated with diminished response to vaccine immunotherapy and poor survival. While GBM-derived soluble factors have been implicated in myeloid PD-L1 expression, the identity of such factors has remained unknown. This study aimed to identify factors responsible for myeloid PD-L1 upregulation as potential targets for immune modulation Experimental Design: Conditioned media from patient-derived GBM explant cell cultures was assessed for cytokine expression and utilized to stimulate naive myeloid cells. Myeloid PD-L1 induction was quantified by flow cytometry. Candidate cytokines correlated with PD-L1 induction were evaluated in tumor sections and plasma for relationships with survival and myeloid PD-L1 expression. The role of identified cytokines on immunosuppression and survival was investigated in vivo utilizing immune competent C57BL/6 mice bearing syngeneic GL261 and CT-2A tumors. RESULTS: GBM-derived interleukin-6 (IL-6) was identified as a cytokine that is necessary and sufficient for myeloid PD-L1 induction in GBM through a signal transducer and activator of transcription 3 (STAT3)-dependent mechanism. Inhibition of IL-6 signaling in orthotopic murine glioma models was associated with reduced myeloid PD-L1 expression, diminished tumor growth, and increased survival. The therapeutic benefit of anti-IL-6 therapy proved to be CD8+ T cell dependent, and the anti-tumor activity was additive with that provided by programmed death-1 (PD-1) targeted immunotherapy. CONCLUSIONS: Our findings suggest that disruption of IL-6 signaling in GBM reduces local and systemic myeloid-driven immunosuppression and enhances immune-mediated anti-tumor responses against GBM.

Author Info: (1) Neurological Surgery, Northwestern University, Feinberg School of Medicine. (2) Neurological Surgery, Northwestern University. (3) Neurological Surgery, Northwestern University

Author Info: (1) Neurological Surgery, Northwestern University, Feinberg School of Medicine. (2) Neurological Surgery, Northwestern University. (3) Neurological Surgery, Northwestern University. (4) Neurosurgery, Barrow Neurological Institute. (5) Neurological Surgery, University of California San Francisco Medical Center. (6) Neurological Surgery, Northwestern University. (7) Neurological Surgery, Northwestern University. (8) Otolaryngology Head and Neck Surgery, Stanford University School of Medicine. (9) Neurosurgery, University of Virginia. (10) Neurological Surgery, Northwestern University. (11) Neurological Surgery, Northwestern University. (12) Neurological Surgery, Northwestern University. (13) Neurological Surgery, Northwestern University. (14) Neurological Surgery, Northwestern University, Feinberg School of Medicine. (15) Pathology, Northwestern University, Feinberg School of Medicine. (16) Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine. (17) Neurological Surgery, Feinberg School of Medicine, Northwestern University. (18) Neurological Surgery, Northwestern University orin.bloch@northwestern.edu.

Regulation of the translation activity of antigen-specific mRNA is responsible for antigen loss and tumor immune escape in a HER2-expressing tumor model

Tumor cells tend to behave differently in response to immune selective conditions. Contrary to those in therapeutic antitumor conditions, tumor cells in prophylactic antitumor conditions lose antigen expression for antitumor immune escape. Here, using a CT26/HER2 tumor model, we investigate the underlying mechanism(s). We selected tumor cell variants (CT26/HER2-A1 and -A2) displaying resistance to antitumor protective immunity and loss of HER2 antigen expression. These immune-resistant cells failed to induce Ag-specific IgG and IFN-gamma responses while forming tumors at the same rate as CT26/HER2 cells. RT-PCR, qRT-PCR, PCR, Western blot and DNA sequencing analyses demonstrated that HER2 expression was inhibited at the post-transcriptional level in these immune-resistant cells, suggesting that tumor cells may escape antitumor immunity through the post-transcriptional regulation of antigen gene expression. The proteasome and lysosomal protein degradation pathways were not responsible for antigen loss, as determined by an inhibitor assay. Finally, HER2 mRNA was found to be not present in the monosomes and polysomes of CT26/HER2-A2 cells, as opposed to CT26/HER2 cells, suggesting that the translation activity of HER2 mRNAs may be suppressed in these immune-resistant cells. Taken together, our results report a new mechanism by which tumor cells respond to antitumor protective immunity for antitumor immune evasion.

Author Info: (1) BIT Medical Convergence Graduate Program and Department of Microbiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 24341, Korea. Gyeonggi-do Insti

Author Info: (1) BIT Medical Convergence Graduate Program and Department of Microbiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 24341, Korea. Gyeonggi-do Institute of Health and Environment, Suwon, Gyeonggi-do, 16205, Korea. (2) BIT Medical Convergence Graduate Program and Department of Microbiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 24341, Korea. (3) Department of Anesthesia and Pain Medicine, Korea Cancer Center Hospital, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Korea. (4) Department of Anesthesia and Pain Medicine, Korea Cancer Center Hospital, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Korea. (5) BIT Medical Convergence Graduate Program and Department of Microbiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 24341, Korea. jsin1964@hanmail.net.

Single-cell RNA sequencing of lung adenocarcinoma reveals heterogeneity of immune response-related genes

Immunotherapy has emerged as a promising approach to treat cancer. However, partial responses across multiple clinical trials support the significance of characterizing intertumor and intratumor heterogeneity to achieve better clinical results and as potential tools in selecting patients for different types of cancer immunotherapies. Yet, the type of heterogeneity that informs clinical outcome and patient selection has not been fully explored. In particular, the lack of characterization of immune response-related genes in cancer cells hinders the further development of metrics to select and optimize immunotherapy. Therefore, we analyzed single-cell RNA-Seq data from lung adenocarcinoma patients and cell lines to characterize the intratumor heterogeneity of immune response-related genes and demonstrated their potential impact on the efficacy of immunotherapy. We discovered that IFN-gamma signaling pathway genes are heterogeneously expressed and coregulated with other genes in single cancer cells, including MHC class II (MHCII) genes. The downregulation of genes in IFN-gamma signaling pathways in cell lines corresponds to an acquired resistance phenotype. Moreover, analysis of 2 groups of tumor-restricted antigens, namely neoantigens and cancer testis antigens, revealed heterogeneity in their expression in single cells. These analyses provide a rationale for applying multiantigen combinatorial therapies to prevent tumor escape and establish a basis for future development of prognostic metrics based on intratumor heterogeneity.

Author Info: (1) Institute for Cellular and Molecular Biology, College of Natural Sciences. (2) Department of Biomedical Engineering, Cockrell School of Engineering, and. (3) Institute for Cell

Author Info: (1) Institute for Cellular and Molecular Biology, College of Natural Sciences. (2) Department of Biomedical Engineering, Cockrell School of Engineering, and. (3) Institute for Cellular and Molecular Biology, College of Natural Sciences. Department of Biomedical Engineering, Cockrell School of Engineering, and. (4) Institute for Cellular and Molecular Biology, College of Natural Sciences. Department of Oncology, LIVESTRONG Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, Texas, USA. Division of Pharmacology/Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA. (5) Department of Oncology, LIVESTRONG Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, Texas, USA. (6) Department of AnoRectal Surgery and. Department of Center Laboratory, the Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China. (7) Institute for Cellular and Molecular Biology, College of Natural Sciences. Department of Biomedical Engineering, Cockrell School of Engineering, and. Department of Oncology, LIVESTRONG Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, Texas, USA.

Cancer associated fibroblasts sculpt tumour microenvironment by recruiting monocytes and inducing immunosuppressive PD-1(+) TAMs

Fibroblasts turn into cancer associated fibroblasts (CAFs) in the tumour microenvironment. CAFs have recently attracted attention for their function as a regulator of immune cell recruitment and function in addition to their tumour-promoting roles. In this study, we aimed to determine the role of CAFs on monocyte recruitment and macrophage polarization in breast cancer. CAFs, which were alpha-SMA expressing fibroblasts in contrast to normal fibroblasts (NFs), effectively recruited monocytes. Recruitment of monocytes by CAFs might be mediated by monocyte chemotactic protein-1 (MCP-1) as well as stromal cell-derived factor-1 (SDF-1) cytokines. CAFs differentiated the recruited monocytes into M2-like macrophages which are capable of exerting their immunosuppressive roles via the PD-1 axis. CAF-educated monocytes exhibited strong immune suppression unlike NF-educated monocytes and enhanced the motility/invasion of breast cancer cells in addition to increasing the expressions of epithelial-mesenchymal transition (EMT)-related genes and vimentin protein in cancer cells. CAF-educated M1 macrophages displayed increased expression of M2 markers and production of anti-inflammatory cytokine IL-10 in contrast to decreased production of pro-inflammatory cytokine IL-12 compared with control M1 macrophages; suggesting that CAFs were also able to induce the trans-differentiation of M1 macrophages to M2 macrophages. We then investigated the relationship between the infiltration of CAFs and tumour associated macrophages (TAMs) using tissue samples obtained from breast cancer patients. High grade of CAFs significantly correlated with the number of TAMs in human breast cancer tissue samples. It was also associated with higher Ki-67 proliferation index, and higher tumour volume. This result is in line with our finding of increased breast cancer cell proliferation due to the effects of CAF-educated monocytes in vitro. Our results concluded that CAFs play pivotal roles in sculpturing the tumour microenvironment in breast cancer, and therapeutic strategies to reverse the CAF-mediated immunosuppressive microenvironment should be taken into consideration.

Author Info: (1) Department of Basic Oncology, Hacettepe University Cancer Institute, Sihhiye, 06100, Ankara, Turkey. (2) Department of Basic Oncology, Hacettepe University Cancer Institute, Si

Author Info: (1) Department of Basic Oncology, Hacettepe University Cancer Institute, Sihhiye, 06100, Ankara, Turkey. (2) Department of Basic Oncology, Hacettepe University Cancer Institute, Sihhiye, 06100, Ankara, Turkey. gurcangunaydin@hacettepe.edu.tr. (3) Department of Basic Oncology, Hacettepe University Cancer Institute, Sihhiye, 06100, Ankara, Turkey. (4) Department of Pathology, Hacettepe University School of Medicine, Sihhiye, 06100, Ankara, Turkey. (5) Department of General Surgery, Hacettepe University School of Medicine, Sihhiye, 06100, Ankara, Turkey. (6) Department of Plastic Reconstructive and Aesthetic Surgery, Hacettepe University School of Medicine, Sihhiye, 06100, Ankara, Turkey. (7) Department of Basic Oncology, Hacettepe University Cancer Institute, Sihhiye, 06100, Ankara, Turkey.