DOCSLIB.ORG

Engineered Marrow Macrophages for Cancer Therapy: Engorgement, Accumulation, Differentiation, and Acquired Immunity

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Engineered Marrow Macrophages for Cancer Therapy: Engorgement, Accumulation, Differentiation, and Acquired Immunity University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2017 Engineered Marrow Macrophages For Cancer Therapy: Engorgement, Accumulation, Differentiation, And Acquired Immunity Cory Alvey University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Pharmacology Commons Recommended Citation Alvey, Cory, "Engineered Marrow Macrophages For Cancer Therapy: Engorgement, Accumulation, Differentiation, And Acquired Immunity" (2017). Publicly Accessible Penn Dissertations. 2164. https://repository.upenn.edu/edissertations/2164 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2164 For more information, please contact [email protected]. Engineered Marrow Macrophages For Cancer Therapy: Engorgement, Accumulation, Differentiation, And Acquired Immunity Abstract The ability of a macrophage to engulf and break down invading cells and other targets provides a first line of immune defense in nearly all tissues. This defining ability ot ‘phagos’ or devour can subsequently activate the entire immune system against foreign and diseased cells, and progress is now being made on a decades-old idea of directing macrophages to phagocytose specific targets such as cancer cells. Physical properties of cancer cells influence phagocytosis and relate via cytoskeleton forces to differentiation pathways in solid tumors. Here, SIRPα on macrophages from mouse and human marrow was inhibited to block recognition of CD47, a ‘marker of self.’ These macrophages were then systemically injected into mice with fluorescent human tumors. Within days, the tumors regressed, and fluorescence analyses showed that the more the SIRPα-inhibited macrophages engulfed, the more they accumulated within tumors. In vitro phagocytosis experiments on transwells revealed that macrophage migration through micropores was inhibited by eating. However, during the 1-2 weeks of tumor residency, donor macrophages quickly differentiated toward non-phagocytic, high-SIRPα tumor associated macrophage. Analyses of macrophages on soft or stiff collagenous gels demonstrated a stiffness-driven upregulation of SIRPα. Tissue stiffness also seems to have a role in the development of cancer. Meta-analyses suggest that genomic variation across tumors scales with the stiffness of the tumor tissue of origin. These genomic changes give rise to neoantigens that are important for the development of monocyte/ macrophage immunotherapies. Indeed, marrow-derived macrophages can phagocytose melanoma cells and present neoantigens leading to the activation of T-cells. Unlike past injections of anti-CD47 which cause anemia, no measurable impact on blood profiles, weight, or development of GvHD was observed from systemic injections of SIRPα-inhibited donor macrophages. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Pharmacology First Advisor Dennis E. Discher Subject Categories Pharmacology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/2164 ENGINEERED MARROW MACROPHAGES FOR CANCER THERAPY: ENGORGEMENT, ACCUMULATION, DIFFERENTIATION, AND ACQUIRED IMMUNITY Cory Michael Alvey A DISSERTATION In Pharmacology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirement for the Degree of Doctor of Philosophy 2017 Supervisor of Dissertation ___________________________ Dr. Dennis E. Discher, Ph.D, Robert D. Bent Professor of Chemical and Biomolecular Engineering Graduate Group Chairperson _________________________________________ Dr. Julie A. Blendy, Ph.D. Professor of Pharmacology Dissertation Committee Dr. Jeffrey M. Field, Ph.D. Professor of Pharmacology Dr. Vladimir Muzykantov, M.D., Ph.D., Professor of Pharmacology Dr. Wenchao Song, Ph.D. Professor of Pharmacology Dr. Ellen Pure, Ph.D. Professor of Biomedical Sciences ENGINEERED MARROW MACROPHAGES FOR CANCER THERAPY: ENGORGEMENT, ACCUMULATION, DIFFERENTIATION, AND ACQUIRED IMMUNITY COPYRIGHT 2017 Cory Michael Alvey ACKNOWLEDGEMENTS I would like to express my sincere gratitude to my mentor and thesis advisor Dr. Dennis Discher for believing in me and taking me in his laboratory to pursue my dissertation. I am fortunate to work with a mentor who is a champion of cross-disciplinary approaches to medical research. Though his approach of, “let’s have three progress updates a day” was intense, it was this tactic that kept me on my toes and allowed me to make great progress with my publications. I am grateful that he was open to many ideas I proposed and allowed me to pursue them. His ability to interact with each of the laboratory members with equal intensity, in addition to his large family, made a strong impression on me. I would also like to thank all members of my thesis committee: Dr. Jeff Fields, Dr. Vladimir Muzykantov, Dr. Wenchao Song, and Dr. Ellen Pure for their guidance and support throughout my graduate career. Each meeting with my committee was productive and helped me significantly with the development of my thesis work. I would like to thank the University of Pennsylvania Pharmacology Program with a specific shout-out to the class of 2017. My first year here was my hardest and you made it easier to push through those difficult times. Within the work environment, I would like to thank my colleagues and friends: Dr. Jerome Irianto, Dr. Lucas Smith, Dr. Manu Tewari, Dr. Dave Dingal, Dr. Nisha Sosale, Dr. Kyle Spinler, Dr. Praful Nair, Charlotte Pfeifer, Yuntao Xia, SangKun Cho, Jake Hsu, and Brandon Hayes for productive discussions on research and other non-work-related matters throughout my time in the Discher laboratory. You made it a pleasure to come iii into work day after day. I couldn’t have asked for better co-workers and friends. Throughout my life, I will never forget the times we shared. I wish you all the best! I would like to give special thanks to my close friend Ian Johnston. I can’t imagine a better person to have shared my hobbies with during my time here in Philadelphia. I hope we stay in contact throughout our lives. I will always consider you family. I would like to express my gratitude to my mentors outside the laboratory for their guidance throughout my professional career. Specifically, I would like to thank Dr. Mas Iimura for his mentorship and friendship throughout my years at Ripon College and beyond. We got to know each other during a time when I made the hardest decisions of my life. I was extremely lucky to have met you and truly believe I would not be where I am or the person I am today without you. I can never thank you enough. Finally, I owe a tremendous amount of gratitude to my family. To one of the most important people in my life, my mom, thank you for believing in me and supporting me throughout my entire life despite being overwhelmed with the dreams I had for myself. You are the strongest person I know and it is your strength that I admire most about you and hope I’ve inherited. You’ve had a hard life and have done far too much for your family with little in return. I will do everything I can to repay you and give you the gratitude you deserve. Lastly, I would like to thank the love of my life, Elizabeth. No matter the sense of accomplishment I feel from my achievements in life, they will never compare to the love I have for you. You will always be the most important person in my life. You are an incredible person and I couldn’t have wished for a better partner with whom to share my life. iv ABSTRACT ENGINEERED MARROW MACROPHAGES FOR CANCER THERAPY: ENGORGEMENT, ACCUMULATION, DIFFERENTIATION, AND ACQUIRED IMMUNITY Cory M. Alvey Dennis E. Discher The ability of a macrophage to engulf and break down invading cells and other targets provides a first line of immune defense in nearly all tissues. This defining ability to ‘phagos’ or devour can subsequently activate the entire immune system against foreign and diseased cells, and progress is now being made on a decades-old idea of directing macrophages to phagocytose specific targets such as cancer cells. Physical properties of cancer cells influence phagocytosis and relate via cytoskeleton forces to differentiation pathways in solid tumors. Here, SIRPα on macrophages from mouse and human marrow was inhibited to block recognition of CD47, a ‘marker of self.’ These macrophages were then systemically injected into mice with fluorescent human tumors. Within days, the tumors regressed, and fluorescence analyses showed that the more the SIRPα-inhibited macrophages engulfed, the more they accumulated within tumors. In vitro phagocytosis experiments on transwells revealed that macrophage migration through micropores was inhibited by eating. However, during the 1-2 weeks of tumor residency, donor macrophages quickly differentiated toward non-phagocytic, high-SIRPα tumor associated macrophage. Analyses of macrophages on soft or stiff collagenous gels demonstrated a stiffness-driven upregulation of SIRPα. Tissue stiffness also seems to have a role in the v development of cancer. Meta-analyses suggest that genomic variation across tumors scales with the stiffness of the tumor tissue of origin. These genomic changes give rise to neoantigens that are important for the development of monocyte/macrophage immunotherapies. Indeed, marrow-derived macrophages can phagocytose melanoma cells and present neoantigens leading to the activation of T-cells. Unlike past injections of anti- CD47 which cause anemia, no measurable
Load more

Recommended publications
  • Cancer Immunology, Immunotherapy Editor-In-Chief: H
    Cancer Immunology, Immunotherapy Editor-in-Chief: H. Dong ▶ 94% of authors who answered a survey reported that they would definitely publish or probably publish in the journal again Since its inception in 1976, Cancer Immunology, Immunotherapy (CII) has reported significant advances in the field of tumor immunology. The journal serves as a forum for new concepts and advances in basic, translational, and clinical cancer immunology and immunotherapy. CII is keen to publish broad-ranging ideas and reviews, results which extend or challenge established paradigms, as well as negative studies which fail to reproduce experiments that support current paradigms, and papers that do succeed in reproducing others’ results in different contexts. Cll is especially interested in papers describing clinical trial designs and outcome regardless of whether they met their designated endpoints or not, and particularly those shedding light on immunological mechanisms. CII is affiliated with the Association for Cancer Immunotherapy (CIMT), Canadian Cancer 12 issues/year Immunotherapy Consortium (CCIC), The Japanese Association for Cancer Immunology (JACI), Network Italiano per la Bioterapia dei Tumori (NIBIT),and Sociedad Española de Inmunologia- Electronic access Grupo Española de InmunoTerapia (SEI-GEIT). ▶ link.springer.com CIMT: http://www.cimt.eu/home Subscription information CCIC: http://www.immunotherapycancer.ca/ ▶ springer.com/librarians JACI: http://www.jaci.jp/eng/index.html NIBIT: http://www.nibit.org/index.php SEI-GEIT: http://www.inmunologia.org/grupos/home.php? UpOm5=M&Upfqym5uom=GK CITIM: http://www.canceritim.org Impact Factor: 6.968 (2020), Journal Citation Reports® On the homepage of Cancer Immunology, Immunotherapy at springer.com you can ▶ Sign up for our Table of Contents Alerts ▶ Get to know the complete Editorial Board ▶ Find submission information.
    [Show full text]
  • Prospects for NK Cell Therapy of Sarcoma
    cancers Review Prospects for NK Cell Therapy of Sarcoma Mieszko Lachota 1 , Marianna Vincenti 2 , Magdalena Winiarska 3, Kjetil Boye 4 , Radosław Zago˙zd˙zon 5,* and Karl-Johan Malmberg 2,6,* 1 Department of Clinical Immunology, Doctoral School, Medical University of Warsaw, 02-006 Warsaw, Poland; [email protected] 2 Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0310 Oslo, Norway; [email protected] 3 Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland; [email protected] 4 Department of Oncology, Oslo University Hospital, 0310 Oslo, Norway; [email protected] 5 Department of Clinical Immunology, Medical University of Warsaw, 02-006 Warsaw, Poland 6 Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, 141 86 Stockholm, Sweden * Correspondence: [email protected] (R.Z.); [email protected] (K.-J.M.) Received: 15 November 2020; Accepted: 9 December 2020; Published: 11 December 2020 Simple Summary: Sarcomas are a group of aggressive tumors originating from mesenchymal tissues. Patients with advanced disease have poor prognosis due to the ineffectiveness of current treatment protocols. A subset of lymphocytes called natural killer (NK) cells is capable of effective surveillance and clearance of sarcomas, constituting a promising tool for immunotherapeutic treatment. However, sarcomas can cause impairment in NK cell function, associated with enhanced tumor growth and dissemination. In this review, we discuss the molecular mechanisms of sarcoma-mediated suppression of NK cells and their implications for the design of novel NK cell-based immunotherapies against sarcoma.
    [Show full text]
  • Immunotherapy, Inflammation and Colorectal Cancer
    cells Review Immunotherapy, Inflammation and Colorectal Cancer Charles Robert Lichtenstern 1,2, Rachael Katie Ngu 1,2, Shabnam Shalapour 1,2,* and Michael Karin 1,2,3 1 Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; karinoffi[email protected] 2 Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA 3 Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA * Correspondence: [email protected] Received: 30 January 2020; Accepted: 3 March 2020; Published: 4 March 2020 Abstract: Colorectal cancer (CRC) is the third most common cancer type, and third highest in mortality rates among cancer-related deaths in the United States. Originating from intestinal epithelial cells in the colon and rectum, that are impacted by numerous factors including genetics, environment and chronic, lingering inflammation, CRC can be a problematic malignancy to treat when detected at advanced stages. Chemotherapeutic agents serve as the historical first line of defense in the treatment of metastatic CRC. In recent years, however, combinational treatment with targeted therapies, such as vascular endothelial growth factor, or epidermal growth factor receptor inhibitors, has proven to be quite effective in patients with specific CRC subtypes. While scientific and clinical advances have uncovered promising new treatment options, the five-year survival rate for metastatic CRC is still low at about 14%. Current research into the efficacy of immunotherapy, particularly immune checkpoint inhibitor therapy (ICI) in mismatch repair deficient and microsatellite instability high (dMMR–MSI-H) CRC tumors have shown promising results, but its use in other CRC subtypes has been either unsuccessful, or not extensively explored.
    [Show full text]
  • Innate Immunity and Inflammation
    ISBTc ‐ Primer on Tumor Immunology and Biological Therapy of Cancer InnateInnate ImmunityImmunity andand InflammationInflammation WillemWillem Overwijk,Overwijk, Ph.D.Ph.D. MDMD AndersonAnderson CancerCancer CenterCenter CenterCenter forfor CancerCancer ImmunologyImmunology ResearchResearch Houston,Houston, TXTX www.allthingsbeautiful.com InnateInnate ImmunityImmunity andand InflammationInflammation • Definitions • Cells and Molecules • Innate Immunity and Inflammation in Cancer • Bad Inflammation • Good Inflammation • Therapeutic Implications InnateInnate ImmunityImmunity andand InflammationInflammation • Definitions • Cells and Molecules • Innate Immunity and Inflammation in Cancer • Bad Inflammation • Good Inflammation • Therapeutic Implications • Innate Immunity: Immunity that is naturally present and is not due to prior sensitization to an antigen; generally nonspecific. It is in contrast to acquired/adaptive immunity. Adapted from Merriam‐Webster Medical Dictionary • Innate Immunity: Immunity that is naturally present and is not due to prior sensitization to an antigen; generally nonspecific. It is in contrast to acquired/adaptive immunity. • Inflammation: a local response to tissue injury – Rubor (redness) – Calor (heat) – Dolor (pain) – Tumor (swelling) Adapted from Merriam‐Webster Medical Dictionary ““InnateInnate ImmunityImmunity”” andand ““InflammationInflammation”” areare vaguevague termsterms •• SpecificSpecific cellcell typestypes andand moleculesmolecules orchestrateorchestrate specificspecific typestypes ofof inflammationinflammation
    [Show full text]
  • Principles of Tumour Immunology
    Principles of tumour immunology Michele Teng Nov 20th 2017, Singapore Cancer Immunoregulation and Immunotherapy Laboratory QIMR Berghofer MRI Brisbane, Australia [email protected] Disclosure Slide • I have received speakers bureau honoria from Merck Sharp & Dohme. Talk Outline 1. Hallmarks of Cancer 2. Cells of the Immune system 3. The Cancer Immunity Cycle - Tumor-associated antigens (TAA), Cellular and Humoral responses to TAA 4. Conceptual developments in the field of tumour immunology - Immunosurveillance and role of innate immunity, immune balance against cancer Sources of slide • Charles Janeway’s Immunobiology text book • Peer-reviewed articles (Pubmed) • Online slides ( URL listed) Cancer Hallmarks of Cancer (2000) Hanahan and Weinberg, Cell 2000 Emerging Hallmarks and Enabling Characteristics Hanahan and Weinberg, Cell 2011 Hallmarks of Cancer (2017) In Vitrogen Immunology (Study of the immune system) Cells of the immune system ILCs –innate lymphoid cells MAITs –Mucosal associated invariant T cells gd T cells – gamma delta T cells (ILCs) (gd, MAIT) Cancer Immunology (Study of the response of the immune system to cancer) The Cancer-Immunity Cycle – Steps to generate an effective anti-tumour response Chen and Mellman Immunity 2013 Not all cell deaths are equal (at priming an immune response) Cells can die in different ways DAMPs Tumour fragments Immunogenic Cell Death (ICD) DAMPs – Damage (Adjuvanticity, Antigenicity) associated molecular patterns Differential requirements for the immunogenicity of cell death TLR4 Nat Rev Immunol. 2017 Feb;17(2):97-111. doi: 10.1038/nri.2016.107. The Cancer-Immunity Cycle Immunity. 2013 Jul 25;39(1):1-10. doi: 10.1016/j.immuni.2013.07.012.
    [Show full text]
  • Natural Killer Cells
    ell Res C ea m rc te h S & f Darji et al., J Stem Cell Res Ther 2018, 8:3 o T h l Journal of e a r n DOI: 10.4172/2157-7633.1000419 a r p u y o J ISSN: 2157-7633 Stem Cell Research & Therapy Review Article Open Access Natural Killer Cells: From Defense to Immunotherapy in Cancer Darji A1, Kaushal A1, Desai N1 and Rajkumar S2* 1Cadila Pharmaceuticals Ltd, 1389, Trasad Road, Dholka, India 2Institute of Science, Nirma University of Science & Technology, Ahmedabad, India Abstract Natural killer (NK) cells are central components of the innate immunity. The numerous mechanisms used by NK cells to regulate and control cancer metastasis’ include interactions with tumor cells via specific receptors and ligands as well as exerting direct cytotoxicity and cytokine-induced effector mechanisms. NK cells are also clinically important and represent a good target for anticancer immune therapy in which the host immune system is harnessed for anticancer activities. They also display impaired functionality and capability to infiltrate tumors in cancer patients. In this review, we provide an overview of our current knowledge on NK cell in oncology and immunotherapy. Although NK cells might appear to be redundant in several conditions of immune challenge in humans, their manipulation seems to hold promise in efforts to promote antitumor immunotherapy. Therefore, efforts to enhance the therapeutic benefits of NK cell-based immunotherapy by developing strategies are the subject of intense research. Keywords: Cancer; Immunology; Immunotherapy; Natural Killer ‘self’ cells which in order controls the initiation of the cytolytic activity cells and avoids the damage of the tissues [6].
    [Show full text]
  • V12p1284.Pdf
    Journal of Cancer 2021, Vol. 12 1284 Ivyspring International Publisher Journal of Cancer 2021; 12(5): 1284-1294. doi: 10.7150/jca.51346 Review The Role of Tumor Associated Macrophages in Hepatocellular Carcinoma Yu Huang1,2,3,4,5*, Wenhao Ge1,2,3,4,5*, Jiarong Zhou1,2,3,4,5, Bingqiang Gao1,2,3,4,5, Xiaohui Qian1,2,3,4,5 and Weilin Wang1,2,3,4,5 1. Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009. 2. Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang 310009. 3. Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, Zhejiang 310009. 4. Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang University, Hangzhou, Zhejiang 310009. 5. Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang 310009. * These authors contributed equally to this work. Corresponding author: Weilin Wang, Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, Zhejiang, China, 310009; E-mail: [email protected]; Tel: +86057187783820; Fax: +86057187068001. © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2020.07.31; Accepted: 2020.12.04; Published: 2021.01.01 Abstract Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and represents a classic paradigm of inflammation-related cancer.
    [Show full text]
  • Course Syllabus
    Please note: Each college and department may have their own requirements, in addition to those stated in the Syllabus Guidelines. PCB 6231 Cancer Biology II – Immunology and Cancer Immunotherapy Course Prerequisites: N/A 95436 001, Credit Hours 4 College of Arts and Sciences, CMMB COURSE SYLLABUS Insert USF Logo here Instructor Name: Amer Beg Semester/Term & Year: Fall 2018 Monday - Class Meeting Days: Wednesday Class Meeting Time: 9:00 am-11:00 am Class Meeting Location: MRC 3065 Lab Meeting Location: N/A Delivery Method: I. Welcome! II. University Course Description This course focuses on cancer immunology with an introduction to cancer immunotherapy. The basics of immune development and function in the context of tumor immunology will be presented in lectures and through discussion of relevant current literature. The course will also introduce current general principles of immunotherapy. Topics include: • Antibody structures • B Cells • T Cells • Antigen Presentation • Myeloid Cells • Toll-Like Receptors • Natural Killer Cells • Tolerance • Complement • Tumor Immunity and the microenvironment • Immune Suppression III. Course Purpose This course provides an understanding of immune system fundamentals and the changes that develop in cancer patients. The course also provides an introduction to cancer immunotherapy principles and current practice. IV. Course Objectives The objectives are to develop an in-depth understanding of the development, function and regulation of the immune system with an emphasis on tumor immunology. This course is aimed at graduate students in Cancer Biology, Immunology, or those in related disciplines who wish to obtain an advanced perspective on immunologic knowledge and current research. 1 V. Student Learning Outcomes At the conclusion of the course students will demonstrate the ability to discuss in-depth the central immune system components and pathways.
    [Show full text]
  • Advances in Cancer Immunology and Immunotherapy
    Global Journal of Medical Research: F Diseases Volume 18 Issue 2 Version 1.0 Year 2018 Type: Double Blind Peer Reviewed International Research Journal Publisher: Global Journals Online ISSN: 2249-4618 & Print ISSN: 0975-5888 Advances in Cancer Immunology and Immunotherapy By Roman Anton The University of Truth and Common Sense, International Abstract- Background: Recent next-step advances in cancer immunology are found on many frontiers: on targeting cancer and cancer niches with specific conjugated conjugated or unconjugated monoclonal antibodies, by activating immune responses via monoclonal antibodies, antigens and vaccines, cytokines, costimulatory pathways and checkpoint modulators, or by adoptive cell transfer, comprising the newly approved CAR T biomedicines, and many combinatorial strategies for an increasing amount of sub- indications. The field has quickly carved out a new 50 billion dollar biologics industry that will double again in only 4-5 years. It is a topic of immense economic, societal, political, scientific, healthcare-related, and biomedical interest. Despite this importance, unbiased, more complete and more holistic overviews of these new markets and biomedicines technologies are widely missing. Methods: Comprehensive listings and a brief market research are used as a basis to systematically summarize all of the approved cancer immune-therapeutics including their prospective sales estimates to structure a more holistic scientific review and in-depth strategy discourse that provides a better understanding from an overview perspective of the recent advances in cancer immunotherapy by revealing both, its progress and bias in a more complete bigger picture including the research itself. Keywords: cancer, immunology, immunotherapy, CAR T, antibodies, ADC, CDC, ADP, bias, review, market, advances.
    [Show full text]
  • Lactate-Mediated Acidification of Tumor Microenvironment Induces Apoptosis of Liver-Resident NK Cells in Colorectal Liver Metastasis
    Published OnlineFirst December 18, 2018; DOI: 10.1158/2326-6066.CIR-18-0481 Research Article Cancer Immunology Research Lactate-Mediated Acidification of Tumor Microenvironment Induces Apoptosis of Liver- Resident NK Cells in Colorectal Liver Metastasis Cathal Harmon1, Mark W. Robinson1,2, Fiona Hand1,3, Dalal Almuaili1, Keno Mentor3, Diarmaid D. Houlihan3, Emir Hoti3, Lydia Lynch1,4, Justin Geoghegan3, and Cliona O'Farrelly1,2 Abstract Colorectal cancer is the third most common malignancy depleted from CRLM tumors. Healthy liver-resident NK cells worldwide, with 1.3 million new cases annually. Metastasis to exposed to TCM underwent apoptosis in vitro, associated with the liver is a leading cause of mortality in these patients. In elevated lactate. Tumor-infiltrating liver-resident NK cells human liver, metastatic cancer cells must evade populations of showed signs of mitochondrial stress, which was recapitulated liver-resident natural killer (NK) cells with potent cytotoxic in vitro by treating liver-resident NK cells with lactic acid. Lactic capabilities. Here, we investigated how these tumors evade acid induced apoptosis by decreasing the intracellular pH of liver NK-cell surveillance. Tissue biopsies were obtained from NK cells, resulting in mitochondrial dysfunction that could be patients undergoing resection of colorectal liver metastasis prevented by blocking mitochondrial ROS accumulation. (CRLM, n ¼ 18), from the tumor, adjacent tissue, and distal CRLM tumors produced lactate, thus decreasing the pH of resection margin. The number and phenotype of liver-resident the tumor microenvironment. Liver-resident NK cells NK cells, at each site, were analyzed by flow cytometry. Tumor- migrating toward the tumor were unable to regulate intracel- conditioned media (TCM) was generated for cytokine and lular pH resulting in mitochondrial stress and apoptosis.
    [Show full text]
  • The Promise of Targeting Macrophages in Cancer Therapy
    Author Manuscript Published OnlineFirst on March 24, 2017; DOI: 10.1158/1078-0432.CCR-16-3122 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. The Promise of Targeting Macrophages in Cancer Therapy. J. Martin Brown, Lawrence Recht and Samuel Strober Departments of Radiation Oncology (JMB.), Neurology (LR), and Medicine (SS) Stanford University, Stanford, CA 94305. Corresponding author J. Martin Brown Department of Neurology, 1201 Welch Road, P254 Stanford, CA 94305 Phone: (415) 730-1190 E-mail: [email protected] Running Title: Benefit of targeting macrophages in cancer therapy Conflict of interest: The authors declare no potential conflicts of interest. Grant Support The study was supported by grants R01 CA149318 (JMB and LR) and R01 CA 163441 (SS). 1 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 24, 2017; DOI: 10.1158/1078-0432.CCR-16-3122 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Cancer therapy has developed around the concept of killing, or stopping the growth of, the cancer cells. Molecularly targeted therapy is the modern expression of this paradigm. Increasingly, however, the realization that the cancer has co-opted the normal cells of the stroma for its own survival has led to the concept that the tumor microenvironment (TME) could be targeted for effective therapy. In this Review we outline the importance of tumor associated macrophages (TAMs), a major component of the TME, in the response of tumors to cancer therapy.
    [Show full text]
  • A Guide to Cancer Immunotherapy: from T Cell Basic Science to Clinical Practice
    REVIEWS A guide to cancer immunotherapy: from T cell basic science to clinical practice Alex D. Waldman 1,2, Jill M. Fritz1,2 and Michael J. Lenardo 1,2 ✉ Abstract | The T lymphocyte, especially its capacity for antigen-directed cytotoxicity, has become a central focus for engaging the immune system in the fight against cancer. Basic science discoveries elucidating the molecular and cellular biology of the T cell have led to new strategies in this fight, including checkpoint blockade, adoptive cellular therapy and cancer vaccinology. This area of immunological research has been highly active for the past 50 years and is now enjoying unprecedented bench-to-bedside clinical success. Here, we provide a comprehensive historical and biological perspective regarding the advent and clinical implementation of cancer immunotherapeutics, with an emphasis on the fundamental importance of T lymphocyte regulation. We highlight clinical trials that demonstrate therapeutic efficacy and toxicities associated with each class of drug. Finally, we summarize emerging therapies and emphasize the yet to be elucidated questions and future promise within the field of cancer immunotherapy. Neoantigens The idea to deploy the immune system as a tool to treat system to prevent carcinogenesis in a manner similar to 1 1 Antigens not expressed by neoplastic disease originated in the nineteenth century . graft rejection . Productive immune responses following self-tissues under normal Wilhelm Busch and Friedrich Fehleisen were the first tumoural adoptive transfer in mice4 and clinical reports conditions that manifest in to describe an epidemiological association between of spontaneous regression of melanoma in patients with the context of pathology; in 5 cancer, these could be altered immune status and cancer.
    [Show full text]