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cancer immunological microenvironment

Shu-Hai Chen, Bing-Yuan Zhang, Bin Zhou, Cheng-Zhan Zhu, Le-Qi Sun, Yu-Jie Feng
Perineural invasion (PNI) can be found in a variety of malignant tumors. It is a sign of tumor metastasis and invasion and portends the poor prognosis of patients. The pathological description and clinical significance of PNI are clearly understood, but exploration of the underlying molecular mechanism is ongoing. It was previously thought that the low-resistance channel in the anatomic region led to the occurrence of PNI. However, with rapid development of precision medicine and molecular biology, we have gradually realized that the occurrence of PNI is not the result of a single factor...
2019: American Journal of Cancer Research
Kelly G Paulson, Miranda Lahman, Aude G Chapuis, Isaac Brownell
Among all tumor types, skin cancers are profoundly sensitive to immunotherapy. Indeed, the recently reported response rates for anti-PD-1 (anti-programmed-death 1) therapy for cutaneous malignant melanomas (MM), Merkel cell carcinomas, basal cell carcinomas, cutaneous squamous cell carcinomas and Kaposi sarcomas are all above 40%. This unique immunogenicity renders skin cancers as a paradigm for tumor-immune interactions and is driven by high mutational burdens, overexpressed tumor antigens and/or viral antigens...
February 8, 2019: International Immunology
A Capasso, J Lang, T M Pitts, K R Jordan, C H Lieu, S L Davis, J R Diamond, S Kopetz, J Barbee, J Peterson, B M Freed, B W Yacob, S M Bagby, W A Messersmith, J E Slansky, R Pelanda, S G Eckhardt
BACKGROUND: The success of agents that reverse T-cell inhibitory signals, such as anti-PD-1/PD-L1 therapies, has reinvigorated cancer immunotherapy research. However, since only a minority of patients respond to single-agent therapies, methods to test the potential anti-tumor activity of rational combination therapies are still needed. Conventional murine xenograft models have been hampered by their immune-compromised status; thus, we developed a hematopoietic humanized mouse model, hu-CB-BRGS, and used it to study anti-tumor human immune responses to triple-negative breast cancer (TNBC) cell line and patient-derived colorectal cancer (CRC) xenografts (PDX)...
February 8, 2019: Journal for Immunotherapy of Cancer
Michael Surace, Karma DaCosta, Anna Huntley, Weiguang Zhao, Christopher Bagnall, Charles Brown, Chichung Wang, Kristin Roman, Jennifer Cann, Arthur Lewis, Keith Steele, Marlon Rebelatto, Edwin R Parra, Clifford C Hoyt, Jaime Rodriguez-Canales
Continued developments in immuno-oncology require an increased understanding of the mechanisms of cancer immunology. The immunoprofiling analysis of tissue samples from formalin-fixed, paraffin-embedded (FFPE) biopsies has become a key tool for understanding the complexity of tumor immunology and discovering novel predictive biomarkers for cancer immunotherapy. Immunoprofiling analysis of tissues requires the evaluation of combined markers, including inflammatory cell subpopulations and immune checkpoints, in the tumor microenvironment...
January 21, 2019: Journal of Visualized Experiments: JoVE
Tess O'Meara, Anton Safonov, David Casadevall, Tao Qing, Andrea Silber, Brigid Killelea, Christos Hatzis, Lajos Pusztai
PURPOSE: African-American (AA) patients with triple-negative breast cancer (TNBC) are less likely to achieve pathologic complete response from neoadjuvant chemotherapy and have poorer prognosis than Caucasian patients with TNBC, suggesting potential biological differences by race. Immune infiltration is the most consistent predictive marker for chemotherapy response and improved prognosis in TNBC. In this study, we test the hypothesis that the immune microenvironment differs between AA and Caucasian patients...
February 6, 2019: Breast Cancer Research and Treatment
Katharina Strasser, Hanna Birnleitner, Andrea Beer, Dietmar Pils, Marlene C Gerner, Klaus G Schmetterer, Thomas Bachleitner-Hofmann, Anton Stift, Michael Bergmann, Rudolf Oehler
T cells in colorectal cancer (CRC) are associated with improved survival. However, checkpoint immunotherapies antagonizing the suppression of these cells are ineffective in the great majority of patients. To better understand the immune cell regulation in CRC, we compared tumor-associated T lymphocytes and macrophages to the immune cell infiltrate of normal mucosa. Human colorectal tumor specimen and tumor-distant normal mucosa tissues of the same patients were collected. Phenotypes and functionality of tissue-derived T cells and macrophages were characterized using immunohistochemistry, RNA in situ hybridization, and multiparameter flow cytometry...
2019: Oncoimmunology
Meromit Singer, Ana C Anderson
It has long been appreciated that tumors are diverse, varying in mutational status, composition of cellular infiltrate, and organizational architecture. For the most part, the information embedded in this diversity has gone untapped due to the limited resolution and dimensionality of assays for analyzing nucleic acid expression in cells. The advent of high-throughput, next-generation sequencing (NGS) technologies that measure nucleic acids, particularly at the single-cell level, is fueling the characterization of the many components that comprise the tumor microenvironment (TME), with a strong focus on immune composition...
February 2019: Cancer Immunology Research
Ryotaro Ogawa, Takamasa Yamamoto, Hideyo Hirai, Keita Hanada, Yoshiyuki Kiyasu, Gen Nishikawa, Rei Mizuno, Susumu Inamoto, Yoshiro Itatani, Yoshiharu Sakai, Kenji Kawada
PURPOSE: SMAD4 is a key transcriptional factor of TGF-b signaling, and acts as a tumor suppressor in colorectal cancer (CRC). In the present study, we explored the immunological effect of SMAD4 on the tumor microenvironment. EXPERIMENTAL DESIGN: Using 99 clinical specimens and human CRC cell lines, we investigate the relationship between SMAD4 expression and neutrophil accumulation. We immunohistochemically analyzed expression of SMAD4, CXCL1, CXCL8, CXCR2 and other proteins with clinical specimens...
January 31, 2019: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Henrique Lemos, Lei Huang, George C Prendergast, Andrew L Mellor
Immune checkpoints arise from physiological changes during tumorigenesis that reprogramme inflammatory, immunological and metabolic processes in malignant lesions and local lymphoid tissues, which constitute the immunological tumour microenvironment (TME). Improving clinical responses to immune checkpoint blockade will require deeper understanding of factors that impact local immune balance in the TME. Elevated catabolism of the amino acids tryptophan (Trp) and arginine (Arg) is a common TME hallmark at clinical presentation of cancer...
January 29, 2019: Nature Reviews. Cancer
Koichi Saruwatari, Ryo Sato, Shunya Nakane, Shinya Sakata, Koutaro Takamatsu, Takayuki Jodai, Remi Mito, Yuko Horio, Sho Saeki, Yusuke Tomita, Takuro Sakagami
BACKGROUND: Anti-programmed cell death 1 (PD-1) monoclonal antibodies (Abs) unleash an immune response to cancer. However, a disruption of the immune checkpoint function by blocking PD-1/PD-ligand 1(PD-L1) signaling may trigger myasthenia gravis (MG) as a life-threatening immune-related adverse event. MG is a neuromuscular disease and is closely associated with being positive for anti-acetylcholine receptor (anti-AChR) Abs, which are high specific and diagnostic Abs for MG. METHODS: A 72-year-old man was diagnosed with chemotherapy-refractory lung squamous cell carcinoma and nivolumab was selected as the third-line regimen...
January 24, 2019: Cancers
Ernest C Borden
Over the past decade, preclinical and clinical research have confirmed the essential role of interferons for effective host immunological responses to malignant cells. Type I interferons (IFNα and IFNβ) directly regulate transcription of >100 downstream genes, which results in a myriad of direct (on cancer cells) and indirect (through immune effector cells and vasculature) effects on the tumour. New insights into endogenous and exogenous activation of type I interferons in the tumour and its microenvironment have given impetus to drug discovery and patient evaluation of interferon-directed strategies...
January 24, 2019: Nature Reviews. Drug Discovery
Chuanlin Ding, Xiaomin Sun, Caijun Wu, Xiaoling Hu, Huang-Ge Zhang, Jun Yan
The role of the mTOR signaling pathway in different myeloid cell subsets is poorly understood in the context of tumor development. In this study, myeloid cell-specific Raptor knockout (KO) mice were used to determine the roles of mechanistic target of rapamycin complex 1 (mTORC1) in regulating macrophage function from Lewis lung carcinoma (LLC) s.c. tumors and lung tumor metastasis. We found no difference in tumor growth between conditional Raptor KO and control mice in the s.c. tumor models, although depletion of mTORC1 decreased the immunosuppressive function of tumor-associated macrophages (TAM)...
January 21, 2019: Journal of Immunology: Official Journal of the American Association of Immunologists
Daniel Shae, Kyle W Becker, Plamen Christov, Dong Soo Yun, Abigail K R Lytton-Jean, Sema Sevimli, Manuel Ascano, Mark Kelley, Douglas B Johnson, Justin M Balko, John T Wilson
Cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) are a promising class of immunotherapeutics that activate innate immunity to increase tumour immunogenicity. However, the efficacy of CDNs is limited by drug delivery barriers, including poor cellular targeting, rapid clearance and inefficient transport to the cytosol where STING is localized. Here, we describe STING-activating nanoparticles (STING-NPs)-rationally designed polymersomes for enhanced cytosolic delivery of the endogenous CDN ligand for STING, 2'3' cyclic guanosine monophosphate-adenosine monophosphate (cGAMP)...
January 21, 2019: Nature Nanotechnology
Qian Chen, Jiawen Chen, Zhijuan Yang, Jun Xu, Ligeng Xu, Chao Liang, Xiao Han, Zhuang Liu
External radiotherapy is extensively used in clinic to destruct tumors by locally applied ionizing-radiation beams. However, the efficacy of radiotherapy is usually limited by tumor hypoxia-associated radiation resistance. Moreover, as a local treatment technique, radiotherapy can hardly control tumor metastases, the major cause of cancer death. Herein, core-shell nanoparticles based poly(lactic-co-glycolic) acid (PLGA) are fabricate, by encapsulating water-soluble catalase (Cat), an enzyme that can decompose H2 O2 to generate O2 , inside the inner core, and loading hydrophobic imiquimod (R837), a Toll-like-receptor-7 agonist, within the PLGA shell...
January 21, 2019: Advanced Materials
Derek Reichel, Manisha Tripathi, J Manuel Perez
Biological interactions between tumor-associated macrophages (TAMs), cancer cells and other cells within the tumor microenvironment contribute to tumorigenesis, tumor growth, metastasis and therapeutic resistance. TAMs can remodel the tumor microenvironment to reduce growth barriers such as the dense extracellular matrix and shift tumors towards an immunosuppressive microenvironment that protects cancer cells from targeted immune responses. Nanoparticles can interrupt these biological interactions within tumors by altering TAM phenotypes through a process called polarization...
2019: Nanotheranostics
Shan Gao, Dongjuan Yang, Yan Fang, Xiaojie Lin, Xuechao Jin, Qi Wang, Xiyan Wang, Liyuan Ke, Kai Shi
Owing to the fast-paced growth and cross-infiltration of oncology, immunology and molecular biology, tumor immunotherapy technology represented by immune checkpoint blockade and chimeric antigen receptor (CAR) T cell therapy has lately made remarkable advancements. In comparison with traditional chemotherapy, immunotherapy has the potential to elicit a stronger sustained antitumor immune response in those patients who have advanced malignant malignancies. In spite of the advancements made, a significant number of clinical research works have validated that an extensive proportion of cancer patients still manifest insensitivity to immunotherapy, primarily because of the immunomodulatory interactions between tumor cells and the immunosuppressive tumor microenvironment (TME), together mediating the immune tolerance of tumors and accordingly impacting the positive response to immunotherapy...
2019: Theranostics
Katarzyna Bednarska-Szczepaniak, Damian Krzyżanowski, Magdalena Klink, Marek Nowak
BACKGROUND: Adenosine released by cancer cells in high amounts in the tumour microenvironment is one of the main immunosuppressive agents responsible for the escape of cancer cells from immunological control. Blocking adenosine receptors with adenosine analogues and restoring immune cell activity is one of the methods considered to increase the effectiveness of anticancer therapy. However, their direct effects on cancer cell biology remain unclear. Here we determined the effect of adenosine analogues on the response of cisplatin-sensitive and cisplatin-resistant ovarian cancer cells to cisplatin treatment...
January 17, 2019: Anti-cancer Agents in Medicinal Chemistry
Maria Sofia Basile, Emanuela Mazzon, Andrea Russo, Santa Mammana, Antonio Longo, Vincenza Bonfiglio, Matteo Fallico, Rosario Caltabiano, Paolo Fagone, Ferdinando Nicoletti, Teresio Avitabile, Michele Reibaldi
Uveal melanoma (UM) is the most common primary intraocular cancer in adults. In the present study, we aimed to characterize the immunological features of primary UM cancer and to provide an association with prognostic markers and outcome. Also, we assessed the influence of the microenvironment on the expression of inhibitory immune checkpoints in UM. Genes of interest included MHC Class I and Class II molecules, as well as inhibitory immune-checkpoints, i.e. PDL1, PDL2, B7-H3, B7-H4, TBFRSF6B, CD47, CD155, GAL9, HVEM and CD200...
2019: PloS One
Aurelie Hanoteau, Jared M Newton, Rosemarie Krupar, Chen Huang, Hsuan-Chen Liu, Angelina Gaspero, Robyn D Gartrell, Yvonne M Saenger, Thomas D Hart, Saskia J Santegoets, Damya Laoui, Chad Spanos, Falguni Parikh, Padmini Jayaraman, Bing Zhang, Sjoerd H Van der Burg, Jo A Van Ginderachter, Cornelis J M Melief, Andrew G Sikora
BACKGROUND: Chemoradiotherapy (CRT) remains one of the most common cancer treatment modalities, and recent data suggest that CRT is maximally effective when there is generation of an anti-tumoral immune response. However, CRT has also been shown to promote immunosuppressive mechanisms which must be blocked or reversed to maximize its immune stimulating effects. METHODS: Therefore, using a preclinical model of human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC), we developed a clinically relevant therapy combining CRT and two existing immunomodulatory drugs: cyclophosphamide (CTX) and the small molecule inducible nitric oxide synthase (iNOS) inhibitor L-n6-(1-iminoethyl)-lysine (L-NIL)...
January 15, 2019: Journal for Immunotherapy of Cancer
Manxue Fu, Liling Tang
BACKGROUND: Chimeric Antigen Receptor (CAR) T cell immunotherapy, as an innovative method for tumor immunotherapy, acquires unprecedented clinical outcomes. Genetic modification not only provides T cells with the antigen-binding function but also endows T cells better immunological functions both in solid and hematological cancer. However, the CAR T cell therapy is not perfect because of several reasons, such as tumor immune microenvironment, and autologous limiting factors of CAR T cells...
January 11, 2019: Recent Patents on Anti-cancer Drug Discovery
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