Immune Response In Tumor Microenvironment Research Articles

Prediction and preventive strategies for recurrence after surgery for hepatocellular carcinoma

Many advances have been achieved in the clinical and basic studies on metastasis and recurrence of hepatocellular carcinoma (HCC) over the past 20 years. The achievements mainly include the following aspects: (1) a group of molecules related to metastasis and recurrence including osteopontin have been identified, and multi-molecular predictive models for metastasis have been established and optimized; (2) it has been found that the imbalance of immune response in tumor microenvironment is important in promoting metastasis and can be used to predict metastasis and recurrence; (3) it has been found and confirmed that interferon can prevent postoperative recurrence, and patients with a lower miR-26a expression level can achieve greater benefits; (4) the breakthroughs in liquid biopsy and immunotherapy bring a promising future for the prediction, prevention, and treatment of HCC metastasis and recurrence. However, these predictive models still need to be validated by multi-center studies, and the effects of adjuvant transarterial chemoembolization and targeted therapy with sorafenib still need further evaluation.

Macrophage migration inhibitory factor promotes breast cancer metastasis via activation of HMGB1/TLR4/NF kappa B axis

Macrophage migration inhibitory factor (MIF) is up-regulated in diverse solid tumors and acts as the critical link between immune response and tumorigenesis. In this study, we demonstrated that MIF overexpression promoted migration of breast cancer cells by elevating TLR4 expression. Further investigation evidenced that MIF induced ROS generation. MIF-induced ROS led to ERK phosphorylation, which facilitated HMGB1 release from the nucleus to the cytoplasm. MIF overexpression also induced caveolin-1 phosphorylation. Caveolin-1 phosphorylation contributed to HMGB1 secretion from the cytoplasm to the extracellular matrix. The extracellular HMGB1 activated TLR4 signaling including NF-κB phosphorylation, which was responsible for the transcription of Snail and Twist as well as MMP2 activation. Furthermore, MIF-induced caveolin-1-dependent HMGB1 secretion might control the recruitment of CD11b+ immune cells. Our data suggested that MIF affected the intrinsic properties of tumors and the host immune response in tumor microenvironment by regulating the TLR4/HMGB1 axis, leading to metastasis of breast cancer.

Establish of heterotopic transplantation of testis in the rat

Purpose: Little is known about how oncogenes affect the immune response in tumor microenvironment (TME). In this study, we focused on how oncogenes modulate adaptive immune response of ovarian cancer with peritoneal carcinomatosis and investigated the difference between reproductive immunity and tumor immunity. Methods: K-ras was stably introduced intomurine ovarian cancer cell line: ID8. Each cell line was intra-peritoneal injected into mice, and the production of ascites was observed. The population of T cell and dendritic cell (DC) subsets of spleen and ascites was assessedbyCD8/CD4orCD11c/mPDCAdouble-stainedflowcytometry. Results: K-ras enhanced the production of ascites. Compared to control mice, the CD8/CD4 ratio was increased in the cancer induced ascites without any difference between ID8 and ID8Kras. CD11c high mPDCA negative DC subset was increased in the ID8-induced ascites, which was markedly decreased in the ID8Kras-induced ascites. There was no significant difference in the subset of T cell or DC of spleen. Conclusion: K-ras accelerated cancer progression by modulating immune response in TME. In the tumor immune system, oncogenes, being closely related to the modulation of TME, are responsible for its specific characteristics compared to the reproductive immunity.

The modulation of adaptive immune response by oncogene K-ras; mouse model of ovarian cancer

Purpose: Little is known about how oncogenes affect the immune response in tumor microenvironment (TME). In this study, we focused on how oncogenes modulate adaptive immune response of ovarian cancer with peritoneal carcinomatosis and investigated the difference between reproductive immunity and tumor immunity. Methods: K-ras was stably introduced intomurine ovarian cancer cell line: ID8. Each cell line was intra-peritoneal injected into mice, and the production of ascites was observed. The population of T cell and dendritic cell (DC) subsets of spleen and ascites was assessedbyCD8/CD4orCD11c/mPDCAdouble-stainedflowcytometry. Results: K-ras enhanced the production of ascites. Compared to control mice, the CD8/CD4 ratio was increased in the cancer induced ascites without any difference between ID8 and ID8Kras. CD11c high mPDCA negative DC subset was increased in the ID8-induced ascites, which was markedly decreased in the ID8Kras-induced ascites. There was no significant difference in the subset of T cell or DC of spleen. Conclusion: K-ras accelerated cancer progression by modulating immune response in TME. In the tumor immune system, oncogenes, being closely related to the modulation of TME, are responsible for its specific characteristics compared to the reproductive immunity.

Translational Insights on Lung Transplantation: Learning from Immunology.

The introduction of ex vivo lung perfusion (EVLP) in the practice of lung transplantation has allowed the reconditioning of the marginal grafts and their conversion into transplantable grafts. In addition, EVLP can provide a platform for the application of various preventive measures to decrease the incidence of post-transplant complications. While the Toronto team targets the attenuation of the cytokine production within the graft through gene therapy to up-regulate IL-10, other measures could be applied to achieve significant attenuation of the cytokine load of the graft. This manuscript provides a short overview on the importance of the attenuation of the cytokine production within the transplanted lung grafts and some possible strategies to achieve this goal.

Inhibition of indoleamine 2,3-dioxygenase 1 expression alters immune response in colon tumor microenvironment in mice.

Indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades the essential amino acid l-tryptophan along the kynurenine pathway, exerts immunomodulatory effects in a number of diseases. IDO expression is increased in tumor tissue and in draining lymph nodes; this increase is thought to play a role in tumor evasion by suppressing the immune response. A competitive inhibitor of IDO is currently being tested in clinical trials for the treatment of relapsed or refractory solid tumors, but the efficacy of IDO inhibition in colorectal tumors remains to be fully elucidated. In this study, we investigated the effect of IDO deficiency on colon tumorigenesis in mice by genetic deletion and pharmacological inhibition. Ido1-deficient(−/−) mice were crossed with ApcMin/+ mice or were administered azoxymethane with or without dextran sodium sulfate. Ido1 deficiency did not lead to significant differences in the size and number of colon tumors. Similarly, the pharmacological inhibition of IDO using 1-methyltryptophan (1-mT) also resulted in no significant differences in tumor size and number in ApcMin/+ mice. However, Ido1 deficiency altered the immune response in the tumor microenvironment, showing a significant increase in mRNA expression of pro-inflammatory cytokines and a significant decrease in the number of Foxp3-positive regulatory T cells in the colon tumors of Ido1(−/−) mice. Importantly, 1-mT treatment also significantly altered cytokine expression in the colon tumor tissues. These results suggest that IDO inhibition alone cannot sufficiently suppress colon cancer development in mice despite its immunomodulatory activity in the tumor microenvironment.

Pam2 lipopeptides systemically increase myeloid-derived suppressor cells through TLR2 signaling

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that exhibit potent immunosuppressive activity. They are increased in tumor-bearing hosts and contribute to tumor development. Toll-like receptors (TLRs) on MDSCs may modulate the tumor-supporting properties of MDSCs through pattern-recognition. Pam2 lipopeptides represented by Pam2CSK4 serve as a TLR2 agonist to exert anti-tumor function by dendritic cell (DC)-priming that leads to NK cell activation and cytotoxic T cell proliferation. On the other hand, TLR2 enhances tumor cell progression/invasion by activating tumor-infiltrating macrophages. How MDSCs respond to TLR2 agonists has not yet been determined. In this study, we found intravenous administration of Pam2CSK4 systemically up-regulated the frequency of MDSCs in EG7 tumor-bearing mice. The frequency of tumor-infiltrating MDSCs was accordingly increased in response to Pam2CSK4. MDSCs were not increased by Pam2CSK4 stimuli in TLR2 knockout (KO) mice. Adoptive transfer experiments using CFSE-labeled MDSCs revealed that the TLR2-positive MDSCs survived long in tumor-bearing mice in response to Pam2CSK4 treatment. Since the increased MDSC population sustained immune-suppressive properties, our study suggests that Pam2CSK4-triggered TLR2 activation enhances the MDSC potential and suppress antitumor immune response in tumor microenvironment.

Hypoxia-inducible factors in regulation of immune responses in tumour microenvironment.

Hypoxia is one of the hallmarks of the tumour microenvironment. It is the result of insufficient blood supply to support proliferating tumour cells. In response to hypoxia, the cellular machinery uses mechanisms whereby the low level of oxygen is sensed and counterbalanced by changing the transcription of numerous genes. Hypoxia-inducible factors (HIF) play a critical role in the regulation of cellular responses to hypoxia. In recent years ample evidence has indicated that HIF play a prominent role in tumour immune responses. Up-regulation of HIF1αpromotes immune suppressive activity of myeloid-derived suppressive cells (MDSC) and tumour-associated macrophages (TAM) and rapid differentiation of MDSC to TAM. HIF1α does not affect MDSC differentiation to dendritic cells (DC) but instead causes DC activation. HIF inhibit effector functions of tumour-infiltrating lymphocytes. HIF1α inhibits regulatory T (Treg) cell development by switching the balance towards T helper type 17 cells. However, as a major part of Treg cell differentiation does not take place in the tumour site, a functionally more important role of HIF1α is in the promotion of Treg cell recruitment to the tumour site in response to chemokines. As a result, the presence of Treg cells inside tumours is increased. Hence, HIF play a largely negative role in the regulation of immune responses inside tumours. It appears that therapeutic strategies targeting HIF in the immune system could be beneficial for anti-tumour immune responses.

SIGIRR as a Novel HER2-Regulated Gene in Breast Tumors

Event Abstract Back to Event SIGIRR as a Novel HER2-Regulated Gene in Breast Tumors Luis Felipe I. Campesato1, 2*, Ana Paula M. Silva1, Fábio C. Navarro1, 2, Marina Marçola3, Regina P. Markus3, Ana Paula Lepique4, Erico T. Costa1 and Anamaria A. Camargo1 1 Hospital Sírio-Libanês, Molecular Oncology Center, Brazil 2 University of São Paulo, Department of Biochemistry, Brazil 3 University of São Paulo, Institute of Biosciences, Brazil 4 University of São Paulo, Institute of Biomedical Sciences, Brazil Introduction: Transcriptional changes associated with overexpression of the receptor tyrosine kinase HER2 in human breast tumors were investigated using an immortalized mammary epithelial cell (HB4a) and its HER2 overexpressing variant (HB4a-C5.2). Global analysis of gene expression identified SIGIRR, a negative modulator of pro-inflammatory signals triggered by IL-1R and TLRs, as an upregulated gene in the C5.2 variant. Given the dual role of inflammation in tumor initiation and progression, we hypothesize that HER2-dependent SIGIRR overexpression in breast tumors may fine-tune inflammation and attenuate the antitumoral adaptive response. Methods and Results: qPCR and Western Blot analysis in C5.2 cells treated with Lapatinib confirmed that SIGIRR upregulation was dependent on HER2 activity. In agreement, bioinformatic analysis of public microarray data confirmed both SIGIRR and HER2 strong correlation. EMSA assays showed that shRNA-mediated knockdown of SIGIRR in C5.2 cells resulted in a 2-fold increase of NFkB activity upon IL-1b stimulation, confirming SIGIRR as a negative modulator of IL1R-dependent NFkB activation. To address the role of SIGIRR upregulation in tumoral milieu we investigated the expression of the cytokines IL-6, IL-8, IFNb, IL12 and TNF-a after IL-1b stimulus. The expression of all the above mentioned cytokines were at least 2 to 3-fold upregulated in SIGIRR knockdown clones and higher levels of IL-6 and IL-8 were also detected in conditioned medium. Higher expression of chemokines CSF2 and CSF3 was also observed in SIGIRR knockdown cells. Conclusion: Our results indicate SIGIRR as a novel HER2-regulated gene that may fine-tune inflammation and adaptive immune response in tumor microenvironment. Support: FAPESP, LICR Keywords: SIGIRR, NFkB, tumor immunology, Tir, HER2/ERBB2 Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Innate immunity Citation: Campesato LI, Silva AM, Navarro FC, Marçola M, Markus RP, Lepique A, Costa ET and Camargo AA (2013). SIGIRR as a Novel HER2-Regulated Gene in Breast Tumors. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00272 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 13 Mar 2013; Published Online: 22 Aug 2013. * Correspondence: Mr. Luis Felipe I Campesato, Hospital Sírio-Libanês, Molecular Oncology Center, São Paulo, Brazil, lfcampesato@mochsl.org.br Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Luis Felipe I Campesato Ana Paula M Silva Fábio C Navarro Marina Marçola Regina P Markus Ana Paula Lepique Erico T Costa Anamaria A Camargo Google Luis Felipe I Campesato Ana Paula M Silva Fábio C Navarro Marina Marçola Regina P Markus Ana Paula Lepique Erico T Costa Anamaria A Camargo Google Scholar Luis Felipe I Campesato Ana Paula M Silva Fábio C Navarro Marina Marçola Regina P Markus Ana Paula Lepique Erico T Costa Anamaria A Camargo PubMed Luis Felipe I Campesato Ana Paula M Silva Fábio C Navarro Marina Marçola Regina P Markus Ana Paula Lepique Erico T Costa Anamaria A Camargo Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

The Role of Signal Transducer and Activator of Transcription 3 (STAT3) in Tumor Immunity

BACKGROUND: Inflammation is a key component of the tumor microenvironment. Cancer-associated inflammation is marked by the presence of specific inflammatory cells and inflammatory mediators. Moreover, immune cells in the tumor microenvironment not only fail to mount an effective antitumor immune response, but also interact intimately with the tumor cells to actively promote oncogenesis.CONTENT: Their roles in regulating cytokine-dependent inflammation and immunity make the signal transducer and activator of transcription (STAT) proteins critical players in determining whether immune responses in tumor microenvironment promote or inhibit cancer. Recent evidence suggests a crucial role for STAT family proteins, especially STAT3 (signal transducer and activator of transcription 3), which is a point of convergence for numerous oncogenic signaling pathways, in selectively inducing and maintaining a procarcinogenic inflammatory microenvironment, both at the initiation of malignant transformation and during cancer progression. The persistent activation of STAT3 increases tumor cell proliferation, survival, and invasion while supressing antitumor immunity. SUMMARY: STAT3 signaling pathway constitutes a potential preventive and therapeutic target for cancer immunotherapy. KEYWORDS: STAT3, inflammation, tumor microenvironment, cancer immunotherapy

Inflammatory Immune Responses in Tumor Microenvironment and Metastasis of Hepatocellular Carcinoma

Metastasis is a multistage process that requires cancer cells to escape from the primary tumor, survive in the circulation, seed at distant sites and grow. Each of these processes involves rate-limiting steps that are influenced by non-malignant cells of the tumor microenvironment. There are growing evidences that tumors are sustained and promoted by inflammatory signals from the surrounding microenvironment. This review describes experimental data demonstrating the role of the inflammatory immune responses of microenvironment in metastases of hepatocellular carcinoma (HCC), points out the prospective areas for future research and possible new therapeutic approaches to control the metastasis of HCC.

Randomized phase II clinical trial to assess MUC1 specific immune response to L-BLP25 vaccine in addition to standard therapy in newly diagnosed high-risk prostate cancer.

TPS4701 Background: In high-risk prostate cancer, radiation therapy (RT) + androgen deprivation therapy (ADT) improve survival. Nonetheless, 10-year disease specific mortality is about 25%. L-BLP25 is a cancer vaccine containing the BLP25 lipopeptide that targets MUC1 tumor antigen. It may enhance immune targeting of cells that express MUC1 (e.g. prostate cancer). In murine models, RT synergizes with vaccine-induced anti-cancer immunity (augments T-cell mediated cancer cytolysis, up-regulates cellular Fas and co-stimulatory/adhesion molecules). ADT augments T-cell trafficking to prostate. Immune response to combining the three (L-BLP25 + RT + ADT) is not known. The current trial intends to study this immune response to L-BLP25 + RT + ADT and compare it to RT+ADT alone. Using ELISPOT, endo-rectal MRI and serial prostate biopsies, this trial was designed to correlate systemic immune response with changes in tumor imaging and/or tumor microenvironment after treatment with L-BLP25. This trial may provide insight into immune response biomarkers that are most appropriate in this setting. Methods: A randomized (1:1), open-label, phase II trial of 42 pts is planned. Eligibility: Adult males with newly diagnosed high-risk prostate cancer (T3 or Gleason ≥ 8 or seminal vesicle involvement or N1 or PSA>20) and HLA-A2/A3 positivity (to allow for ELISPOT analysis). The vaccine arm will receive RT + 2-year ADT + L-BLP25. Standard arm will receive RT + 2-year ADT. L-BLP25 vaccine schedule: biweekly X 5 starting with neo-adjuvant ADT, then 6 weekly X 4 starting with RT. A single 300mg/m2 cyclophosphamide infusion (decreases suppressor T-cells) will be given 3 days before L-BLP25 to enhance immune response in the vaccine arm. The impact of L-BLP25 + RT+ADT on MUC-1-specific systemic immune response will be determined using interval peripheral blood ELISPOT assays. Endo-rectal coil MRI will be done before and after treatment to study prostate signal changes for correlative and predictive analysis. MRI-UltraSound guided lesion-targeted serial prostate biopsies will be obtained to assess immune response in tumor microenvironment. Two pts have been enrolled.