1
|
Su C, Kim SK, Wang CX, Kirsch DG, Monjazeb AM. Radiotherapy Combined with Intralesional Immunostimulatory Agents for Soft Tissue Sarcomas. Semin Radiat Oncol 2024; 34:243-257. [PMID: 38508788 PMCID: PMC11216412 DOI: 10.1016/j.semradonc.2024.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2024]
Abstract
Immunotherapy has shifted the treatment paradigm for many types of cancer. Unfortunately, the most commonly used immunotherapies, such as immune checkpoint inhibitors (ICI), have yielded limited benefit for most types of soft tissue sarcoma (STS). Radiotherapy (RT) is a mainstay of sarcoma therapy and can induce immune modulatory effects. Combining immunotherapy and RT in STS may be a promising strategy to improve sarcoma response to RT and increase the efficacy of immunotherapy. Most combination strategies have employed immunotherapies, such as ICI, that derepress immune suppressive networks. These have yielded only modest results, possibly due to the limited immune stimulatory effects of RT. Combining RT with immune stimulatory agents has yielded promising preclinical and clinical results but can be limited by the toxic nature of systemic administration of immune stimulants. Using intralesional immune stimulants may generate stronger RT immune modulation and less systemic toxicity, which may be a feasible strategy in accessible tumors such as STS. In this review, we summarize the immune modulatory effects of RT, the mechanism of action of various immune stimulants, including toll-like receptor agonists, and data for combinatorial strategies utilizing these agents.
Collapse
Affiliation(s)
- Chang Su
- Department of Radiation Oncology, Duke University, Durham, NC
| | - Soo Kyoung Kim
- Department of Radiation Oncology, UC Davis Comprehensive Cancer Center, UC Davis Health, Davis, CA
| | - Charles X Wang
- Department of Radiation Oncology, UC Davis Comprehensive Cancer Center, UC Davis Health, Davis, CA
| | - David G Kirsch
- Department of Radiation Oncology, Duke University, Durham, NC; Department of Radiation Oncology, Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Arta M Monjazeb
- Department of Radiation Oncology, UC Davis Comprehensive Cancer Center, UC Davis Health, Davis, CA.
| |
Collapse
|
2
|
Wu H, Lin J, Ling N, Zhang Y, He Y, Qiu L, Tan W. Functional Nucleic Acid-Based Immunomodulation for T Cell-Mediated Cancer Therapy. ACS NANO 2024; 18:119-135. [PMID: 38117770 DOI: 10.1021/acsnano.3c09861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2023]
Abstract
T cell-mediated immunity plays a pivotal role in cancer immunotherapy. The anticancer actions of T cells are coordinated by a sequence of biological processes, including the capture and presentation of antigens by antigen-presenting cells (APCs), the activation of T cells by APCs, and the subsequent killing of cancer cells by activated T cells. However, cancer cells have various means to evade immune responses. Meanwhile, these vulnerabilities provide potential targets for cancer treatments. Functional nucleic acids (FNAs) make up a class of synthetic nucleic acids with specific biological functions. With their diverse functionality, good biocompatibility, and high programmability, FNAs have attracted widespread interest in cancer immunotherapy. This Review focuses on recent research progress in employing FNAs as molecular tools for T cell-mediated cancer immunotherapy, including corresponding challenges and prospects.
Collapse
Affiliation(s)
- Hui Wu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), The Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Jie Lin
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China
| | - Neng Ling
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China
| | - Yutong Zhang
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China
| | - Yao He
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China
| | - Liping Qiu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), The Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China
| | - Weihong Tan
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), The Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China
- Institute of Molecular Medicine (IMM), Renji Hospital, Shanghai Jiao Tong University School of Medicine, College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| |
Collapse
|
3
|
Chakraborty S, Ye J, Wang H, Sun M, Zhang Y, Sang X, Zhuang Z. Application of toll-like receptors (TLRs) and their agonists in cancer vaccines and immunotherapy. Front Immunol 2023; 14:1227833. [PMID: 37936697 PMCID: PMC10626551 DOI: 10.3389/fimmu.2023.1227833] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 10/10/2023] [Indexed: 11/09/2023] Open
Abstract
Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) expressed in various immune cell types and perform multiple purposes and duties involved in the induction of innate and adaptive immunity. Their capability to propagate immunity makes them attractive targets for the expansion of numerous immunotherapeutic approaches targeting cancer. These immunotherapeutic strategies include using TLR ligands/agonists as monotherapy or combined therapeutic strategies. Several TLR agonists have demonstrated significant efficacy in advanced clinical trials. In recent years, multiple reports established the applicability of TLR agonists as adjuvants to chemotherapeutic drugs, radiation, and immunotherapies, including cancer vaccines. Cancer vaccines are a relatively novel approach in the field of cancer immunotherapy and are currently under extensive evaluation for treating different cancers. In the present review, we tried to deliver an inclusive discussion of the significant TLR agonists and discussed their application and challenges to their incorporation into cancer immunotherapy approaches, particularly highlighting the usage of TLR agonists as functional adjuvants to cancer vaccines. Finally, we present the translational potential of rWTC-MBTA vaccination [irradiated whole tumor cells (rWTC) pulsed with phagocytic agonists Mannan-BAM, TLR ligands, and anti-CD40 agonisticAntibody], an autologous cancer vaccine leveraging membrane-bound Mannan-BAM, and the immune-inducing prowess of TLR agonists as a probable immunotherapy in multiple cancer types.
Collapse
Affiliation(s)
- Samik Chakraborty
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
- NE1 Inc., New York, NY, United States
| | - Juan Ye
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Herui Wang
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Mitchell Sun
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Yaping Zhang
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Xueyu Sang
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Zhengping Zhuang
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| |
Collapse
|
4
|
Klinman DM, Goguet E, Tross D. TLR Agonist Therapy of Metastatic Breast Cancer in Mice. J Immunother 2023; 46:170-177. [PMID: 37103328 PMCID: PMC10168108 DOI: 10.1097/cji.0000000000000467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 03/20/2023] [Indexed: 04/28/2023]
Abstract
Toll-like receptor (TLR) 7/8 and 9 agonists stimulate an innate immune response that supports the development of tumor-specific immunity. Previous studies showed that either agonist individually could cure mice of small tumors and that when used in combination, they could prevent the progression of larger tumors (>300 mm 3 ). To examine whether these agents combined could control metastatic disease, syngeneic mice were challenged with the highly aggressive 66cl4 triple-negative breast tumor cell line. Treatment was not initiated until pulmonary metastases were established, as verified by bioluminescent imaging of luciferase-tagged tumor cells. Results show that combined therapy with TLR7/8 and TLR9 agonists delivered to both primary and metastatic tumor sites significantly reduced tumor burden and extended survival. The inclusion of cyclophosphamide and anti-PD-L1 resulted in optimal tumor control, characterized by a 5-fold increase in the average duration of survival.
Collapse
|
5
|
Jain A, Mittal S, Tripathi LP, Nussinov R, Ahmad S. Host-pathogen protein-nucleic acid interactions: A comprehensive review. Comput Struct Biotechnol J 2022; 20:4415-4436. [PMID: 36051878 PMCID: PMC9420432 DOI: 10.1016/j.csbj.2022.08.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 08/01/2022] [Accepted: 08/01/2022] [Indexed: 12/02/2022] Open
Abstract
Recognition of pathogen-derived nucleic acids by host cells is an effective host strategy to detect pathogenic invasion and trigger immune responses. In the context of pathogen-specific pharmacology, there is a growing interest in mapping the interactions between pathogen-derived nucleic acids and host proteins. Insight into the principles of the structural and immunological mechanisms underlying such interactions and their roles in host defense is necessary to guide therapeutic intervention. Here, we discuss the newest advances in studies of molecular interactions involving pathogen nucleic acids and host factors, including their drug design, molecular structure and specific patterns. We observed that two groups of nucleic acid recognizing molecules, Toll-like receptors (TLRs) and the cytoplasmic retinoic acid-inducible gene (RIG)-I-like receptors (RLRs) form the backbone of host responses to pathogen nucleic acids, with additional support provided by absent in melanoma 2 (AIM2) and DNA-dependent activator of Interferons (IFNs)-regulatory factors (DAI) like cytosolic activity. We review the structural, immunological, and other biological aspects of these representative groups of molecules, especially in terms of their target specificity and affinity and challenges in leveraging host-pathogen protein-nucleic acid interactions (HP-PNI) in drug discovery.
Collapse
Affiliation(s)
- Anuja Jain
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India
| | - Shikha Mittal
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India
- Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Solan, Himachal Pradesh, 173234, India
| | - Lokesh P. Tripathi
- National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan
- Riken Center for Integrative Medical Sciences, Tsurumi, Yokohama, Kanagawa, Japan
| | - Ruth Nussinov
- Computational Structural Biology Section, Basic Science Program, Frederick National, Laboratory for Cancer Research, Frederick, MD 21702, USA
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Israel
| | - Shandar Ahmad
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India
| |
Collapse
|
6
|
Lee W, Suresh M. Vaccine adjuvants to engage the cross-presentation pathway. Front Immunol 2022; 13:940047. [PMID: 35979365 PMCID: PMC9376467 DOI: 10.3389/fimmu.2022.940047] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 07/08/2022] [Indexed: 11/13/2022] Open
Abstract
Adjuvants are indispensable components of vaccines for stimulating optimal immune responses to non-replicating, inactivated and subunit antigens. Eliciting balanced humoral and T cell-mediated immunity is paramount to defend against diseases caused by complex intracellular pathogens, such as tuberculosis, malaria, and AIDS. However, currently used vaccines elicit strong antibody responses, but poorly stimulate CD8 cytotoxic T lymphocyte (CTL) responses. To elicit potent CTL memory, vaccines need to engage the cross-presentation pathway, and this requirement has been a crucial bottleneck in the development of subunit vaccines that engender effective T cell immunity. In this review, we focus on recent insights into DC cross-presentation and the extent to which clinically relevant vaccine adjuvants, such as aluminum-based nanoparticles, water-in oil emulsion (MF59) adjuvants, saponin-based adjuvants, and Toll-like receptor (TLR) ligands modulate DC cross-presentation efficiency. Further, we discuss the feasibility of using carbomer-based adjuvants as next generation of adjuvant platforms to elicit balanced antibody- and T-cell based immunity. Understanding of the molecular mechanism of DC cross-presentation and the mode of action of adjuvants will pave the way for rational design of vaccines for infectious diseases and cancer that require balanced antibody- and T cell-based immunity.
Collapse
|
7
|
Hartimath SV, Ramasamy B, Xuan TY, Rong TJ, Khanapur S, Cheng P, Hwang YY, Robins EG, Goggi JL. Granzyme B PET Imaging in Response to In Situ Vaccine Therapy Combined with αPD1 in a Murine Colon Cancer Model. Pharmaceutics 2022; 14:pharmaceutics14010150. [PMID: 35057046 PMCID: PMC8779135 DOI: 10.3390/pharmaceutics14010150] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/16/2021] [Accepted: 01/04/2022] [Indexed: 12/12/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) block checkpoint receptors that tumours use for immune evasion, allowing immune cells to target and destroy cancer cells. Despite rapid advancements in immunotherapy, durable response rates to ICIs remains low. To address this, combination clinical trials are underway assessing whether adjuvants can enhance responsiveness by increasing tumour immunogenicity. CpG-oligodeoxynucleotides (CpG-ODN) are synthetic DNA fragments containing an unmethylated cysteine-guanosine motif that stimulate the innate and adaptive immune systems by engaging Toll-like receptor 9 (TLR9) present on the plasmacytoid dendritic cells (pDCs) and B cells. Here, we have assessed the ability of AlF-mNOTA-GZP, a peptide tracer targeting granzyme B, to serve as a PET imaging biomarker in response to CpG-ODN 1585 in situ vaccine therapy delivered intratumourally (IT) or intraperitoneally (IP) either as monotherapy or in combination with αPD1. [18F]AlF-mNOTA-GZP was able to differentiate treatment responders from non-responders based on tumour uptake. Furthermore, [18F]AlF-mNOTA-GZP showed positive associations with changes in tumour-associated lymphocytes expressing GZB, namely GZB+ CD8+ T cells, and decreases in suppressive F4/80+ cells. [18F]AlF-mNOTA-GZP tumour uptake was mediated by GZB expressing CD8+ cells and successfully stratifies therapy responders from non-responders, potentially acting as a non-invasive biomarker for ICIs and combination therapy evaluation in a clinical setting.
Collapse
Affiliation(s)
- Siddesh V. Hartimath
- Laboratory of Radiochemistry & Molecular Imaging (LRMI), Institute of Bioengineering and Bioimaging (IBB), A*STAR Research Entities, Helios, Singapore 138667, Singapore; (B.R.); (T.Y.X.); (T.J.R.); (S.K.); (P.C.); (E.G.R.)
- Correspondence: (S.V.H.); (J.L.G.)
| | - Boominathan Ramasamy
- Laboratory of Radiochemistry & Molecular Imaging (LRMI), Institute of Bioengineering and Bioimaging (IBB), A*STAR Research Entities, Helios, Singapore 138667, Singapore; (B.R.); (T.Y.X.); (T.J.R.); (S.K.); (P.C.); (E.G.R.)
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur 56000, Malaysia
| | - Tan Yun Xuan
- Laboratory of Radiochemistry & Molecular Imaging (LRMI), Institute of Bioengineering and Bioimaging (IBB), A*STAR Research Entities, Helios, Singapore 138667, Singapore; (B.R.); (T.Y.X.); (T.J.R.); (S.K.); (P.C.); (E.G.R.)
| | - Tang Jun Rong
- Laboratory of Radiochemistry & Molecular Imaging (LRMI), Institute of Bioengineering and Bioimaging (IBB), A*STAR Research Entities, Helios, Singapore 138667, Singapore; (B.R.); (T.Y.X.); (T.J.R.); (S.K.); (P.C.); (E.G.R.)
| | - Shivashankar Khanapur
- Laboratory of Radiochemistry & Molecular Imaging (LRMI), Institute of Bioengineering and Bioimaging (IBB), A*STAR Research Entities, Helios, Singapore 138667, Singapore; (B.R.); (T.Y.X.); (T.J.R.); (S.K.); (P.C.); (E.G.R.)
| | - Peter Cheng
- Laboratory of Radiochemistry & Molecular Imaging (LRMI), Institute of Bioengineering and Bioimaging (IBB), A*STAR Research Entities, Helios, Singapore 138667, Singapore; (B.R.); (T.Y.X.); (T.J.R.); (S.K.); (P.C.); (E.G.R.)
| | - You Yi Hwang
- FACS facility, Singapore Immunology Network (SIgN), A*STAR Research Entities, Immunos, Singapore 138665, Singapore;
| | - Edward G. Robins
- Laboratory of Radiochemistry & Molecular Imaging (LRMI), Institute of Bioengineering and Bioimaging (IBB), A*STAR Research Entities, Helios, Singapore 138667, Singapore; (B.R.); (T.Y.X.); (T.J.R.); (S.K.); (P.C.); (E.G.R.)
- Clinical Imaging Research Centre (CIRC), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
| | - Julian L. Goggi
- Laboratory of Radiochemistry & Molecular Imaging (LRMI), Institute of Bioengineering and Bioimaging (IBB), A*STAR Research Entities, Helios, Singapore 138667, Singapore; (B.R.); (T.Y.X.); (T.J.R.); (S.K.); (P.C.); (E.G.R.)
- Correspondence: (S.V.H.); (J.L.G.)
| |
Collapse
|
8
|
Subtil B, Cambi A, Tauriello DVF, de Vries IJM. The Therapeutic Potential of Tackling Tumor-Induced Dendritic Cell Dysfunction in Colorectal Cancer. Front Immunol 2021; 12:724883. [PMID: 34691029 PMCID: PMC8527179 DOI: 10.3389/fimmu.2021.724883] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 09/14/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer-related deaths worldwide. Locally advanced and metastatic disease exhibit resistance to therapy and are prone to recurrence. Despite significant advances in standard of care and targeted (immuno)therapies, the treatment effects in metastatic CRC patients have been modest. Untreatable cancer metastasis accounts for poor prognosis and most CRC deaths. The generation of a strong immunosuppressive tumor microenvironment (TME) by CRC constitutes a major hurdle for tumor clearance by the immune system. Dendritic cells (DCs), often impaired in the TME, play a critical role in the initiation and amplification of anti-tumor immune responses. Evidence suggests that tumor-mediated DC dysfunction is decisive for tumor growth and metastasis initiation, as well as for the success of immunotherapies. Unravelling and understanding the complex crosstalk between CRC and DCs holds promise for identifying key mechanisms involved in tumor progression and spread that can be exploited for therapy. The main goal of this review is to provide an overview of the current knowledge on the impact of CRC-driven immunosuppression on DCs phenotype and functionality, and its significance for disease progression, patient prognosis, and treatment response. Moreover, present knowledge gaps will be highlighted as promising opportunities to further understand and therapeutically target DC dysfunction in CRC. Given the complexity and heterogeneity of CRC, future research will benefit from the use of patient-derived material and the development of in vitro organoid-based co-culture systems to model and study DCs within the CRC TME.
Collapse
Affiliation(s)
- Beatriz Subtil
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Alessandra Cambi
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Daniele V. F. Tauriello
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - I. Jolanda M. de Vries
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| |
Collapse
|
9
|
Hangai S, Kimura Y, Taniguchi T, Yanai H. Signal-transducing innate receptors in tumor immunity. Cancer Sci 2021; 112:2578-2591. [PMID: 33570784 PMCID: PMC8253268 DOI: 10.1111/cas.14848] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 02/05/2021] [Accepted: 02/09/2021] [Indexed: 12/15/2022] Open
Abstract
The signal‐transducing innate receptors represent classes of pattern recognition receptors (PRRs) that play crucial roles in the first line of the host defense against infections by the recognition of pathogen‐derived molecules. Because of their poorly discriminative nature compared with antigen receptors of the adaptive immune system, they also recognize endogenous molecules and evoke immune responses without infection, resulting in the regulation of tumor immunity. Therefore, PRRs may be promising targets for effective cancer immunotherapy, either by activating or inhibiting them. Here, we summarize our current knowledge of signal‐transducing PRRs in the regulation of tumor immunity.
Collapse
Affiliation(s)
- Sho Hangai
- Department of Inflammology, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Yoshitaka Kimura
- Department of Inflammology, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Tadatsugu Taniguchi
- Department of Inflammology, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Hideyuki Yanai
- Department of Inflammology, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| |
Collapse
|
10
|
Loira-Pastoriza C, Vanvarenberg K, Ucakar B, Machado Franco M, Staub A, Lemaire M, Renauld JC, Vanbever R. Encapsulation of a CpG oligonucleotide in cationic liposomes enhances its local antitumor activity following pulmonary delivery in a murine model of metastatic lung cancer. Int J Pharm 2021; 600:120504. [PMID: 33753161 DOI: 10.1016/j.ijpharm.2021.120504] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 03/03/2021] [Accepted: 03/14/2021] [Indexed: 01/05/2023]
Abstract
Immunotherapy brings new hope to the fight against lung cancer. General immunostimulatory agents represent an immunotherapy strategy that has demonstrated efficacy with limited toxicity when delivered intratumorally. The goal of this study was to enhance the antitumor efficacy of unmethylated oligodeoxynucleotides containing CpG motifs (CpG) and polyinosinic-polycytidylic acid (poly I:C) double-stranded RNA following their local delivery in lung cancer by encapsulating them in liposomes. Liposomes encapsulation of nucleic acids could increase their uptake by lung phagocytes and thereby the activation of toll-like receptors within endosomes. Liposomes were prepared using a cationic lipid, dioleoyltrimethylammoniumpropane (DOTAP), and dipalmitoylphosphatidylcholine (DPPC), the main phospholipid in lung surfactant. The liposomes permanently entrapped CpG but could not efficiently withhold poly I:C. Both poly I:C and CpG delayed tumor growth in the murine B16F10 model of metastatic lung cancer. However, only CpG increased IFN-γ levels in the lungs. Pulmonary administration of CpG was superior to its intraperitoneal injection to slow the growth of lung metastases and to induce the production of granzyme B, a pro-apoptotic protein, and IFNγ, MIG and RANTES, T helper type 1 cytokines and chemokines, in the lungs. These antitumor activities of CpG were strongly enhanced by CpG encapsulation in DOTAP/DPPC liposomes. Delivery of low CpG doses to the lungs induced increased inflammation markers in the airspaces but the inflammation did not reach the systemic compartment in a significant manner. These data support the use of a delivery carrier to strengthen CpG antitumor activity following its pulmonary delivery in lung cancer.
Collapse
Affiliation(s)
- Cristina Loira-Pastoriza
- Université catholique de Louvain (UCLouvain), Louvain Drug Research Institute, Advanced Drug Delivery & Biomaterials, Brussels, Belgium
| | - Kevin Vanvarenberg
- Université catholique de Louvain (UCLouvain), Louvain Drug Research Institute, Advanced Drug Delivery & Biomaterials, Brussels, Belgium
| | - Bernard Ucakar
- Université catholique de Louvain (UCLouvain), Louvain Drug Research Institute, Advanced Drug Delivery & Biomaterials, Brussels, Belgium
| | - Maria Machado Franco
- Université catholique de Louvain (UCLouvain), Louvain Drug Research Institute, Advanced Drug Delivery & Biomaterials, Brussels, Belgium
| | - Aurélie Staub
- Université catholique de Louvain (UCLouvain), Louvain Drug Research Institute, Advanced Drug Delivery & Biomaterials, Brussels, Belgium
| | - Muriel Lemaire
- UCLouvain, de Duve Institute, Experimental Medicine Unit, Brussels, Belgium
| | | | - Rita Vanbever
- Université catholique de Louvain (UCLouvain), Louvain Drug Research Institute, Advanced Drug Delivery & Biomaterials, Brussels, Belgium.
| |
Collapse
|
11
|
Balneger N, Kroesen M, Lindau D, Wassink M, Boon L, den Brok MH, Büll C, Adema GJ. Generation of αCD11b-CpG antibody conjugates for the targeted stimulation of myeloid cells. J Control Release 2021; 332:148-159. [PMID: 33609622 DOI: 10.1016/j.jconrel.2021.02.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 02/11/2021] [Accepted: 02/13/2021] [Indexed: 10/22/2022]
Abstract
CpG oligonucleotides are short single-stranded synthetic DNA molecules. Upon binding to Toll-like receptor 9 (TLR9), CpG activates immune cells in humans and mice. This results in robust Th1 type immunity potentially resulting in clearance of pathogens, reduction of allergy and anti-tumor immunity. However, the effectiveness of CpG as an adjuvant depends on its administration route, with only strong effects seen when CpG is administered locally. As local administration is not always feasible, we generated conjugates to specifically deliver CpG to myeloid cells often abundantly present in tumors. For this we coupled CpG (3'-Thiol-modified phosphorothioate (PTO) CpG-ODN1826 type B (5'-tccatgacgttcctgacgtt-3')) to monoclonal antibodies (mAbs) directed against the myeloid cell marker CD11b using maleimide-thiol coupling. The CD11b-CpG mAb (αCD11b-CpG) conjugates contained about four CpG molecules/conjugate and displayed binding and internalization characteristics similar to unconjugated CD11b mAbs (αCD11b). The αCD11b-CpG conjugates readily induced maturation of murine dendritic cells (DCs) in a TLR9-dependent manner in vitro. Following intravenous injection, αCD11b-CpG conjugates efficiently targeted CD11b+ immune cells in the blood, lymph nodes and spleen. Finally, injection of αCD11b-CpG conjugates, but not untargeted conjugates, induced maturation of CD11b+ cell subsets in vivo. In conclusion, conjugating CpG to αCD11b enabled specific targeting and activation of myeloid cells in vivo.
Collapse
Affiliation(s)
- N Balneger
- Radiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA Nijmegen, the Netherlands
| | - M Kroesen
- Radiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA Nijmegen, the Netherlands; Holland Proton Therapy Center, Delft, the Netherlands
| | - D Lindau
- Radiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA Nijmegen, the Netherlands; Henkel IP and Holding GmbH, Henkelstr. 67, 40589 Duesseldorf, Germany
| | - M Wassink
- Radiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA Nijmegen, the Netherlands
| | - L Boon
- Bioceros BV, Yalelaan 46, 3584 CM Utrecht, the Netherlands
| | - M H den Brok
- Radiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA Nijmegen, the Netherlands
| | - C Büll
- Radiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA Nijmegen, the Netherlands
| | - G J Adema
- Radiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA Nijmegen, the Netherlands.
| |
Collapse
|
12
|
Wang F, Ma Z, Zhong Y, Salazar F, Xu C, Ren F, Qu L, Wu AM, Dai H. In vivo NIR-II structured-illumination light-sheet microscopy. Proc Natl Acad Sci U S A 2021; 118:e2023888118. [PMID: 33526701 PMCID: PMC8017937 DOI: 10.1073/pnas.2023888118] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Noninvasive optical imaging with deep tissue penetration depth and high spatiotemporal resolution is important to longitudinally studying the biology at the single-cell level in live mammals, but has been challenging due to light scattering. Here, we developed near-infrared II (NIR-II) (1,000 to 1,700 nm) structured-illumination light-sheet microscopy (NIR-II SIM) with ultralong excitation and emission wavelengths up to ∼1,540 and ∼1,700 nm, respectively, suppressing light scattering to afford large volumetric three-dimensional (3D) imaging of tissues with deep-axial penetration depths. Integrating structured illumination into NIR-II light-sheet microscopy further diminished background and improved spatial resolution by approximately twofold. In vivo oblique NIR-II SIM was performed noninvasively for 3D volumetric multiplexed molecular imaging of the CT26 tumor microenvironment in mice, longitudinally mapping out CD4, CD8, and OX40 at the single-cell level in response to immunotherapy by cytosine-phosphate-guanine (CpG), a Toll-like receptor 9 (TLR-9) agonist combined with OX40 antibody treatment. NIR-II SIM affords an additional tool for noninvasive volumetric molecular imaging of immune cells in live mammals.
Collapse
Affiliation(s)
- Feifei Wang
- Department of Chemistry, Stanford University, Stanford, CA 94305
- Bio-X, Stanford University, Stanford, CA 94305
| | - Zhuoran Ma
- Department of Chemistry, Stanford University, Stanford, CA 94305
- Bio-X, Stanford University, Stanford, CA 94305
| | - Yeteng Zhong
- Department of Chemistry, Stanford University, Stanford, CA 94305
- Bio-X, Stanford University, Stanford, CA 94305
| | - Felix Salazar
- Molecular Imaging and Therapy, Beckman Research Institute, City of Hope, Duarte, CA 91010
| | - Chun Xu
- Department of Chemistry, Stanford University, Stanford, CA 94305
- Bio-X, Stanford University, Stanford, CA 94305
| | - Fuqiang Ren
- Department of Chemistry, Stanford University, Stanford, CA 94305
- Bio-X, Stanford University, Stanford, CA 94305
| | - Liangqiong Qu
- School of Medicine, Stanford University, Stanford, CA 94303
| | - Anna M Wu
- Molecular Imaging and Therapy, Beckman Research Institute, City of Hope, Duarte, CA 91010
| | - Hongjie Dai
- Department of Chemistry, Stanford University, Stanford, CA 94305;
- Bio-X, Stanford University, Stanford, CA 94305
| |
Collapse
|
13
|
Abstract
CpG oligonucleotides stimulate via TLR9 and enhance anti-tumor immunity, an effect attributed to the activation of NK and CD8+ T cells. Our recent work demonstrates that CpG ODN also induce monocytic myeloid-derived suppressor cells to mature into M1 macrophages, further aiding tumor elimination. This provides insight into the mechanism through which CpG promote tumor regression.
Collapse
Affiliation(s)
- Hidekazu Shirota
- Cancer and Inflammation Program; National Cancer Institute; Frederick, MD USA ; Basic Science Program; SAIC-Frederick, Inc.; Frederick, MD USA
| | | |
Collapse
|
14
|
Lin AY, Rink JS, Karmali R, Xu J, Kocherginsky M, Thaxton CS, Gordon LI. Tri-ethylene glycol modified class B and class C CpG conjugated gold nanoparticles for the treatment of lymphoma. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2020; 30:102290. [PMID: 32798731 DOI: 10.1016/j.nano.2020.102290] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 08/01/2020] [Accepted: 08/07/2020] [Indexed: 11/17/2022]
Abstract
CpG oligodeoxynucleotides (CpGs) can induce an anti-tumor immune response, but also uniquely cause direct lymphoma cytotoxicity. To improve the delivery and efficacy of CpGs, we utilized a tri-ethylene modified CpG conjugated gold nanoparticle (tmCpG NP) platform that is compatible with both class B and class C CpGs, to treat various types of lymphoma, including diffuse large B cell lymphoma, high-grade lymphoma, Burkitt's lymphoma, and mantle cell lymphoma. Both classes of tmCpG NPs reduced viability of human and murine lymphoma cells via apoptosis compared with free CpGs, while having no toxic effects on dendritic cells. TmCpG NPs increased CD19, CD20, and OX40 expression on the lymphoma cells. Overall, we introduced a stable tmCpG NP design that has significant anti-lymphoma effects.
Collapse
Affiliation(s)
- Adam Yuh Lin
- Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.
| | - Jonathan Scott Rink
- Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Reem Karmali
- Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Jiahui Xu
- Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Masha Kocherginsky
- Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Colby Shad Thaxton
- Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA; Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Leo I Gordon
- Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| |
Collapse
|
15
|
Perry JL, Tian S, Sengottuvel N, Harrison EB, Gorentla BK, Kapadia CH, Cheng N, Luft JC, Ting JPY, DeSimone JM, Pecot CV. Pulmonary Delivery of Nanoparticle-Bound Toll-like Receptor 9 Agonist for the Treatment of Metastatic Lung Cancer. ACS NANO 2020; 14:7200-7215. [PMID: 32463690 PMCID: PMC7531260 DOI: 10.1021/acsnano.0c02207] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
CpG oligodeoxynucleotides are potent toll-like receptor (TLR) 9 agonists and have shown promise as anticancer agents in preclinical studies and clinical trials. Binding of CpG to TLR9 initiates a cascade of innate and adaptive immune responses, beginning with activation of dendritic cells and resulting in a range of secondary effects that include the secretion of pro-inflammatory cytokines, activation of natural killer cells, and expansion of T cell populations. Recent literature suggests that local delivery of CpG in tumors results in superior antitumor effects as compared to systemic delivery. In this study, we utilized PRINT (particle replication in nonwetting templates) nanoparticles as a vehicle to deliver CpG into murine lungs through orotracheal instillations. In two murine orthotopic metastasis models of non-small-cell lung cancer-344SQ (lung adenocarcinoma) and KAL-LN2E1 (lung squamous carcinoma), local delivery of PRINT-CpG into the lungs effectively promoted substantial tumor regression and also limited systemic toxicities associated with soluble CpG. Furthermore, cured mice were completely resistant to tumor rechallenge. Additionally, nanodelivery showed extended retention of CpG within the lungs as well as prolonged elevation of antitumor cytokines in the lungs, but no elevated levels of proinflammatory cytokines in the serum. These results demonstrate that PRINT-CpG is a potent nanoplatform for local treatment of lung cancer that has collateral therapeutic effects on systemic disease and an encouraging toxicity profile and may have the potential to treat lung metastasis of other cancer types.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | - Jenny P-Y Ting
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina 27695, United States
| | - Joseph M DeSimone
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina 27695, United States
| | | |
Collapse
|
16
|
Evaluation of cell surface reactive immuno-adjuvant in combination with immunogenic cell death inducing drug for in situ chemo-immunotherapy. J Control Release 2020; 322:519-529. [PMID: 32243973 PMCID: PMC7262586 DOI: 10.1016/j.jconrel.2020.03.029] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 02/21/2020] [Accepted: 03/20/2020] [Indexed: 12/27/2022]
Abstract
Apoptotic cells and cell fragments, especially those produced as a result of immunogenic cell death (ICD), are known to be a potential source of cancer vaccine immunogen. However, due to variation between tumours and between individuals, methods to generate such preparations may require extensive ex vivo personalisation. To address this, we have utilised the concept of in situ vaccination whereby an ICD inducing drug is injected locally to generate immunogenic apoptotic fragments/cells. These fragments are then adjuvanted by a co-administered cell reactive CpG adjuvant. We first evaluate means of labelling tumour cells with CpG adjuvant, we then go on to demonstrate in vitro that labelling is preserved following apoptosis and, furthermore, that the apoptotic body-adjuvant complexes are readily transferred to macrophages. In in vivo studies we observe synergistic tumour growth delays and elevated levels of CD4+ and CD8+ cells in tumours receiving adjuvant drug combination. CD4+/CD8+ cells are likewise elevated in the tumour draining lymph node and activated to a greater extent than individual treatments. This study represents the first steps toward the evaluation of rationally formulated drug-adjuvant combinations for in situ chemo-immunotherapy.
Collapse
|
17
|
Javaid N, Choi S. Toll-like Receptors from the Perspective of Cancer Treatment. Cancers (Basel) 2020; 12:E297. [PMID: 32012718 PMCID: PMC7072551 DOI: 10.3390/cancers12020297] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 01/22/2020] [Accepted: 01/25/2020] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) represent a family of pattern recognition receptors that recognize certain pathogen-associated molecular patterns and damage-associated molecular patterns. TLRs are highly interesting to researchers including immunologists because of the involvement in various diseases including cancers, allergies, autoimmunity, infections, and inflammation. After ligand engagement, TLRs trigger multiple signaling pathways involving nuclear factor-κB (NF-κB), interferon-regulatory factors (IRFs), and mitogen-activated protein kinases (MAPKs) for the production of various cytokines that play an important role in diseases like cancer. TLR activation in immune as well as cancer cells may prevent the formation and growth of a tumor. Nonetheless, under certain conditions, either hyperactivation or hypoactivation of TLRs supports the survival and metastasis of a tumor. Therefore, the design of TLR-targeting agonists as well as antagonists is a promising immunotherapeutic approach to cancer. In this review, we mainly describe TLRs, their involvement in cancer, and their promising properties for anticancer drug discovery.
Collapse
Affiliation(s)
| | - Sangdun Choi
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea;
| |
Collapse
|
18
|
Vanpouille-Box C, Hoffmann JA, Galluzzi L. Pharmacological modulation of nucleic acid sensors - therapeutic potential and persisting obstacles. Nat Rev Drug Discov 2019; 18:845-867. [PMID: 31554927 DOI: 10.1038/s41573-019-0043-2] [Citation(s) in RCA: 140] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/09/2019] [Indexed: 02/08/2023]
Abstract
Nucleic acid sensors, primarily TLR and RLR family members, as well as cGAS-STING signalling, play a critical role in the preservation of cellular and organismal homeostasis. Accordingly, deregulated nucleic acid sensing contributes to the origin of a diverse range of disorders, including infectious diseases, as well as cardiovascular, autoimmune and neoplastic conditions. Accumulating evidence indicates that normalizing aberrant nucleic acid sensing can mediate robust therapeutic effects. However, targeting nucleic acid sensors with pharmacological agents, such as STING agonists, presents multiple obstacles, including drug-, target-, disease- and host-related issues. Here, we discuss preclinical and clinical data supporting the potential of this therapeutic paradigm and highlight key limitations and possible strategies to overcome them.
Collapse
Affiliation(s)
- Claire Vanpouille-Box
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.,Sandra and Edward Meyer Cancer Center, New York, NY, USA
| | - Jules A Hoffmann
- University of Strasbourg Institute for Advanced Studies, Strasbourg, France.,CNRS UPR 9022, Institute for Molecular and Cellular Biology, Strasbourg, France.,Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA. .,Sandra and Edward Meyer Cancer Center, New York, NY, USA. .,Department of Dermatology, Yale School of Medicine, New Haven, CT, USA. .,Université Paris Descartes, Paris, France.
| |
Collapse
|
19
|
Suek N, Campesato LF, Merghoub T, Khalil DN. Targeted APC Activation in Cancer Immunotherapy to Enhance the Abscopal Effect. Front Immunol 2019; 10:604. [PMID: 31001249 PMCID: PMC6454083 DOI: 10.3389/fimmu.2019.00604] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 03/07/2019] [Indexed: 12/31/2022] Open
Abstract
In oncology, the “abscopal effect” refers to the therapeutic effect on a distant tumor resulting from the treatment of local tumor (e. g., ablation, injection, or radiation). Typically associated with radiation, the abscopal effect is thought to be mediated by a systemic antitumor immune response that is induced by two concurrent changes at the treated tumor: (1) the release of tumor antigens and (2) the exposure of damage-associated molecular patterns. Therapies that produce these changes are associated with immunogenic cell death (ICD). Some interventions have been shown to cause an abscopal effect without inducing the release of tumor antigens, suggesting that release of tumor antigens at baseline plays a significant role in mediating the abscopal effect. With tumor antigens already present, therapies that target activation of APCs alone may be sufficient to enhance the abscopal effect. Here, we discuss two therapies targeted at APC activation, TLR9 and CD40 agonists, and their use in the clinic to enhance the abscopal effect.
Collapse
Affiliation(s)
- Nathan Suek
- Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Luis Felipe Campesato
- Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Taha Merghoub
- Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, United States.,Department of Medicine, Weill Cornell Medical College, New York, NY, United States
| | - Danny N Khalil
- Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, United States.,Department of Medicine, Weill Cornell Medical College, New York, NY, United States
| |
Collapse
|
20
|
Shetab Boushehri MA, Abdel-Mottaleb MMA, Béduneau A, Pellequer Y, Lamprecht A. A nanoparticle-based approach to improve the outcome of cancer active immunotherapy with lipopolysaccharides. Drug Deliv 2018; 25:1414-1425. [PMID: 29902933 PMCID: PMC6058527 DOI: 10.1080/10717544.2018.1469684] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
This study sought to develop a simple nanoparticle-based approach to enhance the efficiency and tolerability of lipopolysaccharide (LPS), a potent ligand of Toll-like Receptor 4 (TLR4), for immunotherapy in cancer. Despite holding promise within this context, the strong pro-inflammatory properties of LPS also account for its low tolerability given localized and systemic side effects, which restrict the administrable dosage. Herein, we investigated the effect of LPS decoration as a surface-active molecule on a polymeric matrix upon its efficiency and tolerability. The LPS-decorated nanoparticles (LPS-NP) were about 150 nm in size, with slightly negative zeta potential (about -15 mV) and acceptable LPS incorporation (about 70%). In vitro, the particles accounted for a higher induction of apoptosis in tumor cells cultured with murine splenocytes compared to LPS solution. When used for the treatment of a murine syngeneic colorectal tumor model, higher intratumoral deposition of the particle-bound LPS was observed. Furthermore, unlike LPS solution, which accounted for localized necrosis at high concentrations, treatment of tumor-bearing animals with equivalent doses of LPS-NP was well tolerated. We propose that the observed localized necrosis can be Shwartzman phenomenon, which, due to modulated 24-h post-injection systemic TNF-α and LPS concentrations, have been avoided in case of LPS-NP. This has in turn enhanced the therapeutic efficiency and enabled complete tumor regression at concentrations at which LPS solution was intolerable. The findings indicate that nanoparticles can serve as beyond carriers for the delivery of superficially decorated LPS molecules, but impact their overall efficiency and tolerability in cancer therapy.
Collapse
Affiliation(s)
| | - Mona M A Abdel-Mottaleb
- a Department of Pharmaceutics , University of Bonn , Bonn , Germany.,b Laboratory of Pharmaceutical Engineering (EA4267) , University of Franche-Comté , Besançon , France.,c Department of Pharmaceutics and Industrial Pharmacy , Faculty of Pharmacy, Ain Shams University , Cairo , Egypt
| | - Arnaud Béduneau
- b Laboratory of Pharmaceutical Engineering (EA4267) , University of Franche-Comté , Besançon , France
| | - Yann Pellequer
- b Laboratory of Pharmaceutical Engineering (EA4267) , University of Franche-Comté , Besançon , France
| | - Alf Lamprecht
- a Department of Pharmaceutics , University of Bonn , Bonn , Germany.,b Laboratory of Pharmaceutical Engineering (EA4267) , University of Franche-Comté , Besançon , France
| |
Collapse
|
21
|
Frank MJ, Reagan PM, Bartlett NL, Gordon LI, Friedberg JW, Czerwinski DK, Long SR, Hoppe RT, Janssen R, Candia AF, Coffman RL, Levy R. In Situ Vaccination with a TLR9 Agonist and Local Low-Dose Radiation Induces Systemic Responses in Untreated Indolent Lymphoma. Cancer Discov 2018; 8:1258-1269. [PMID: 30154192 PMCID: PMC6171524 DOI: 10.1158/2159-8290.cd-18-0743] [Citation(s) in RCA: 145] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 07/13/2018] [Accepted: 08/09/2018] [Indexed: 11/16/2022]
Abstract
This multicenter phase I/II clinical trial evaluated intratumoral SD-101, a TLR9 agonist, and low-dose radiation in patients with untreated indolent lymphoma. Twenty-nine enrolled patients received 4 Gy of radiation followed by 5 weekly intratumoral injections of SD-101 at a single tumor site. No treatment-related grade 4 or serious adverse events occurred. Nearly all patients had tumor reduction at their treated site. More importantly, 24 patients had tumor reduction at their nontreated sites, with 5 patients achieving a partial response and one achieving a complete response. Treatment-related increases of CD8+ and CD4+ effector T cells and decreases of T follicular helper and T regulatory cells (Treg) were observed in the tumor microenvironment. Low pretreatment levels of CD4+ Tregs, proliferating CD8+ T cells, and Granzyme B+ CD8+ T cells were associated with favorable outcomes. Intratumoral SD-101 in combination with low-dose radiation is well tolerated and results in regression of both treated and untreated sites of disease.Significance: In situ vaccination with the TLR9 agonist SD-101, along with low-dose radiation, was safe and induced systemic responses in patients with indolent lymphoma. Low levels of CD4+ Tregs, proliferating CD8+ T cells, and Granzyme B+ CD8+ T cells in the tumor microenvironment predicted favorable response to treatment. Cancer Discov; 8(10); 1258-69. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1195.
Collapse
Affiliation(s)
- Matthew J Frank
- Stanford University Hospital and Clinics, Division of Oncology, Stanford, California
| | | | - Nancy L Bartlett
- Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri
| | - Leo I Gordon
- Feinberg School of Medicine, Northwestern University and the Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois
| | | | - Debra K Czerwinski
- Stanford University Hospital and Clinics, Division of Oncology, Stanford, California
| | - Steven R Long
- Stanford University Hospital and Clinics, Division of Oncology, Stanford, California
| | - Richard T Hoppe
- Stanford University Hospital and Clinics, Department of Radiation Oncology, Stanford, California
| | | | | | | | - Ronald Levy
- Stanford University Hospital and Clinics, Division of Oncology, Stanford, California.
| |
Collapse
|
22
|
Lin WC, Wang WH, Lin YH, Leu JD, Cheng SY, Chen YJ, Hwang JJ. Synergistic effects of tetrandrine combined with ionizing radiation on a murine colorectal carcinoma‑bearing mouse model. Oncol Rep 2018; 40:1390-1400. [PMID: 30015952 PMCID: PMC6072404 DOI: 10.3892/or.2018.6568] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 07/06/2018] [Indexed: 12/27/2022] Open
Abstract
Tetrandrine (TET), a traditional Chinese clinical agent, has been used for the treatment of many diseases, including cancers. The purpose of the present study was to investigate the combined effects of TET and ionizing radiation (IR) on murine CT26 colorectal adenocarcinoma cells in vitro and in vivo. A CT26 cell line transfected with dual HSV-1 thymidine kinase and firefly luciferase (luc) reporter genes was used. The half-maximal inhibitory concentration (IC50) of TET in CT26/tk-luc cells was ~10 µM. An additive effect was observed after combination of both agents based on a colony formation assay. Apoptosis and cleaved caspase-3 levels were increased significantly in cells after combination treatment, as shown by flow cytometric analysis, DNA fragmentation and western blotting. However, tumor growth inhibition and therapeutic efficacy of TET combined with IR in vivo were identified to be synergistic, as monitored by tumor growth delay time, measured with a digital caliper. A significant inhibition of tumor growth was identified in the combination group compared with the radiation only group. Furthermore, non-invasive bioluminescent imaging (BLI) and gamma scintigraphy were also used to evaluate therapeutic efficacy. Both modalities revealed that the best tumor growth control was under combination treatment among all groups. The present study demonstrated that TET is not only beneficial for chemotherapy, but also has potential as a radiosensitizer for the treatment of cancer.
Collapse
Affiliation(s)
- Wei-Chan Lin
- Department of Radiology, Cathay General Hospital, Taipei 106, Taiwan, R.O.C
| | - Wei-Hsun Wang
- Department of Medical Imaging and Radiology, Shu‑Zen Junior College of Medicine and Management, Kaohsiung 821, Taiwan, R.O.C
| | - Yi-Hsien Lin
- Department of Radiation Oncology, Cheng Hsien General Hospital, Bei‑tou, Taipei 112, Taiwan, R.O.C
| | - Jyh-Der Leu
- Department of Radiation Oncology, Taipei City Hospital, Renai Branch, Taipei 242, Taiwan, R.O.C
| | - Shan-Yun Cheng
- Department of Biomedical Imaging and Radiological Sciences, National Yang‑Ming University, Taipei 112, Taiwan, R.O.C
| | - Yu-Jen Chen
- Department of Radiation Oncology, Mackay Memorial Hospital, Taipei 104, Taiwan, R.O.C
| | - Jeng-Jong Hwang
- Department of Biomedical Imaging and Radiological Sciences, National Yang‑Ming University, Taipei 112, Taiwan, R.O.C
| |
Collapse
|
23
|
Bavananthasivam J, Alkie TN, Astill J, Abdul-Careem MF, Wootton SK, Behboudi S, Yitbarek A, Sharif S. In ovo administration of Toll-like receptor ligands encapsulated in PLGA nanoparticles impede tumor development in chickens infected with Marek's disease virus. Vaccine 2018; 36:4070-4076. [PMID: 29859800 DOI: 10.1016/j.vaccine.2018.05.091] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 04/20/2018] [Accepted: 05/21/2018] [Indexed: 01/17/2023]
Abstract
One of the economically important diseases in the poultry industry is Marek's disease (MD) which is caused by Marek's disease virus (MDV). The use of current vaccines provides protection against clinical signs of MD in chickens. However, these vaccines do not prevent the transmission of MDV to susceptible hosts, hence they may promote the development of new virulent strains of MDV. This issue persuaded us to explore alternative approaches to control MD in chickens. Induction of innate responses at the early stage of life in the chicken may help to prevent or reduce MDV infection. Further, prophylactic use of Toll-like receptor ligands (TLR-Ls) has been shown to generate host immunity against infectious diseases. In this regard, encapsulation of TLR-Ls in Poly(d, l-lactic-co-glycolic acid) (PLGA) may further enhance host responses by controlled release of TLR-Ls for an extended period. Hence, in the current study, protective effects of encapsulated TLR4 and TLR21 ligands, LPS and CpG, respectively, were investigated against MD. Results indicated that administration of encapsulated CpG and LPS first at embryonic day (ED) 18, followed by post-hatch at 14 days-post infection (dpi) intramuscularly, diminished tumor incidence by 60% and 42.8%, respectively at 21dpi compared to the MDV only group. In addition, analysis of cytokine gene profiles of interferon (IFN)-α, IFN-β, IFN-γ, inducible nitric oxide synthase (iNOS), interleukin (IL)-1β, IL-18 and IL-10 in spleen and bursa of Fabricius at different time points suggests that TLR-Ls possibly triggered host responses through the expression of IL-1β and IL-18 to reduce tumor formation. However, further studies are needed to explore the role of these pro-inflammatory cytokines and other influencing elements like lymphocytes in the hindrance of tumor development by TLR-Ls treatment in chickens.
Collapse
Affiliation(s)
- Jegarubee Bavananthasivam
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 2W1, Canada
| | - Tamiru N Alkie
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 2W1, Canada
| | - Jake Astill
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 2W1, Canada
| | - Mohamed Faizal Abdul-Careem
- Department of Ecosystem and Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada
| | - Sarah K Wootton
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 2W1, Canada
| | - Shahriar Behboudi
- The Pirbright Institute, Ash Road, Pirbright, Woking, Surrey GU24 0NF, United Kingdom; Department of Pathology and Infectious Disease, School of Veterinary Medicine, University of Surrey, Guildford, United Kingdom
| | - Alexander Yitbarek
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 2W1, Canada
| | - Shayan Sharif
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
| |
Collapse
|
24
|
Hangai S, Kimura Y, Taniguchi T, Yanai H. Innate Immune Receptors in the Regulation of Tumor Immunity. Oncoimmunology 2018. [DOI: 10.1007/978-3-319-62431-0_25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
|
25
|
Radiation-enhanced delivery of systemically administered amphiphilic-CpG oligodeoxynucleotide. J Control Release 2017; 266:248-255. [PMID: 28987882 DOI: 10.1016/j.jconrel.2017.09.043] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 09/26/2017] [Accepted: 09/29/2017] [Indexed: 01/04/2023]
Abstract
Along with vaccines and checkpoint blockade, immune adjuvants may have an important role in tumor immunotherapy. Oligodeoxynucleotides containing unmethylated cytidyl guanosyl dinucleotide motifs (CpG ODN) are TLR9 ligands with attractive immunostimulatory properties, but intratumoral administration has been required to induce an effective anti-tumor immune response. Following on recent studies with radiation-targeted delivery of nanoparticles, we examined enhanced tumor-specific delivery of amphiphile-CpG, an albumin-binding analog of CpG ODN, following systemic administration 3days after tumor irradiation. The combination of radiation and CpG displayed superior tumor control over either treatment alone. Intravital imaging of fluorescently labeled amphiphilic-CpG revealed increased accumulation in irradiated tumors along with decreased off-target accumulation in visceral organs. Within 48h after amphiphile-CpG administration, immune activation could be detected by increased Granzyme B and Interferon gamma activity in the tumor as well as in circulating monocytes and activated CD8+ T cells. Using radiotherapy to enhance the targeting of CpG to tumors may help advance this once promising therapy to clinical relevance.
Collapse
|
26
|
Baird JR, Monjazeb AM, Shah O, McGee H, Murphy WJ, Crittenden MR, Gough MJ. Stimulating Innate Immunity to Enhance Radiation Therapy-Induced Tumor Control. Int J Radiat Oncol Biol Phys 2017; 99:362-373. [PMID: 28871985 PMCID: PMC5604475 DOI: 10.1016/j.ijrobp.2017.04.014] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 04/02/2017] [Indexed: 12/29/2022]
Abstract
Novel ligands that target Toll-like receptors and other innate recognition pathways represent a potent strategy for modulating innate immunity to generate antitumor immunity. Although many of the current clinically successful immunotherapies target adaptive T-cell responses, both preclinical and clinical studies suggest that adjuvants have the potential to enhance the scope and efficacy of cancer immunotherapy. Radiation may be a particularly good partner to combine with innate immune therapies, because it is a highly efficient means to kill cancer cells but may fail to send the appropriate inflammatory signals needed to act as an efficient endogenous vaccine. This may explain why although radiation therapy is a highly used cancer treatment, true abscopal effects-regression of disease outside the field without additional systemic therapy-are extremely rare. This review focuses on efforts to combine innate immune stimuli as adjuvants with radiation, creating a distinct and complementary approach from T cell-targeted therapies to enhance antitumor immunity.
Collapse
Affiliation(s)
- Jason R Baird
- Earle A. Chiles Research Institute, Providence Cancer Center, Portland, Oregon
| | - Arta M Monjazeb
- Department of Radiation Oncology, UC Davis Comprehensive Cancer Center, Sacramento, California; Laboratory of Cancer Immunology, UC Davis Comprehensive Cancer Center, Sacramento, California
| | - Omid Shah
- Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Heather McGee
- Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - William J Murphy
- Laboratory of Cancer Immunology, UC Davis Comprehensive Cancer Center, Sacramento, California
| | - Marka R Crittenden
- Earle A. Chiles Research Institute, Providence Cancer Center, Portland, Oregon; The Oregon Clinic, Portland, Oregon
| | - Michael J Gough
- Earle A. Chiles Research Institute, Providence Cancer Center, Portland, Oregon.
| |
Collapse
|
27
|
Forkhead box-P3 + regulatory T cells and toll-like receptor 2 co-expression in oral squamous cell carcinoma. Acta Histochem 2017; 119:205-210. [PMID: 28174027 DOI: 10.1016/j.acthis.2016.12.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 12/22/2016] [Accepted: 12/23/2016] [Indexed: 01/08/2023]
Abstract
BACKGROUND The function of forkhead box-P3 (FoxP3) regulatory T cells (Treg) and toll-like receptor (TLR)2 protein in the oral cancer microenvironment is not fully understood, but evidence from other malignancies suggests it is likely they are involved with tumour development and progression. The aim of this study was to investigate the distribution of FoxP3+cells, TLR2+ cells and double-labelled FoxP3+TLR2+ immune cells in oral squamous cell carcinoma (OSCC), using immunohistochemistry (IHC) and immunofluorescence (IF). METHODS 25 archival cases of OSCC were immunostained with anti-FoxP3 and anti-TLR2 antibodies. Inflamed hyperplastic oral mucosal tissues were used as controls. The proportion of single-labelled, double-labelled and negative cells was determined. RESULTS A higher frequency of double-labelled FoxP3+TLR2+ Tregs was observed within the immune cells of OSCC compared to inflamed controls using IHC (p<0.05). Cell-to-cell contact between single-stained TLR2+ cells and FoxP3+ cells was noted. Double IF studies validated demonstration of co-expression of FoxP3+/TLR2+ immune cells in OSCC. CONCLUSION The presence of FoxP3+TLR2+ cells within the OSCC microenvironment may represent a dendritic cell-dependent pathway capable of inhibiting Treg suppressive activity, potentially enhancing the anti-tumour response. Modulation of TLR2-Treg interactions should be further explored to determine if they have a role in the therapeutic management of OSCC.
Collapse
|
28
|
Abstract
Organisms throughout biology need to maintain the integrity of their genome. From bacteria to vertebrates, life has established sophisticated mechanisms to detect and eliminate foreign genetic material or to restrict its function and replication. Tremendous progress has been made in the understanding of these mechanisms which keep foreign or unwanted nucleic acids from viruses or phages in check. Mechanisms reach from restriction-modification systems and CRISPR/Cas in bacteria and archaea to RNA interference and immune sensing of nucleic acids, altogether integral parts of a system which is now appreciated as nucleic acid immunity. With inherited receptors and acquired sequence information, nucleic acid immunity comprises innate and adaptive components. Effector functions include diverse nuclease systems, intrinsic activities to directly restrict the function of foreign nucleic acids (e.g., PKR, ADAR1, IFIT1), and extrinsic pathways to alert the immune system and to elicit cytotoxic immune responses. These effects act in concert to restrict viral replication and to eliminate virus-infected cells. The principles of nucleic acid immunity are highly relevant for human disease. Besides its essential contribution to antiviral defense and restriction of endogenous retroelements, dysregulation of nucleic acid immunity can also lead to erroneous detection and response to self nucleic acids then causing sterile inflammation and autoimmunity. Even mechanisms of nucleic acid immunity which are not established in vertebrates are relevant for human disease when they are present in pathogens such as bacteria, parasites, or helminths or in pathogen-transmitting organisms such as insects. This review aims to provide an overview of the diverse mechanisms of nucleic acid immunity which mostly have been looked at separately in the past and to integrate them under the framework nucleic acid immunity as a basic principle of life, the understanding of which has great potential to advance medicine.
Collapse
Affiliation(s)
- G Hartmann
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, Bonn, Germany.
| |
Collapse
|
29
|
Gardner A, Ruffell B. Dendritic Cells and Cancer Immunity. Trends Immunol 2016; 37:855-865. [PMID: 27793569 DOI: 10.1016/j.it.2016.09.006] [Citation(s) in RCA: 644] [Impact Index Per Article: 71.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Revised: 09/23/2016] [Accepted: 09/27/2016] [Indexed: 02/06/2023]
Abstract
Dendritic cells (DCs) are central regulators of the adaptive immune response, and as such are necessary for T-cell-mediated cancer immunity. In particular, antitumoral responses depend on a specialized subset of conventional DCs that transport tumor antigens to draining lymph nodes and cross-present antigen to activate cytotoxic T lymphocytes. DC maturation is necessary to provide costimulatory signals to T cells, but while DC maturation occurs within tumors, it is often insufficient to induce potent immunity, particularly in light of suppressive mechanisms within tumors. Bypassing suppressive pathways or directly activating DCs can unleash a T-cell response, and although clinical efficacy has proven elusive, therapeutic targeting of DCs continues to hold translational potential in combinatorial approaches.
Collapse
Affiliation(s)
- Alycia Gardner
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Cancer Biology PhD Program, University of South Florida, Tampa, FL, USA
| | - Brian Ruffell
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
| |
Collapse
|
30
|
Mohamed W, Domann E, Chakraborty T, Mannala G, Lips KS, Heiss C, Schnettler R, Alt V. TLR9 mediates S. aureus killing inside osteoblasts via induction of oxidative stress. BMC Microbiol 2016; 16:230. [PMID: 27716055 PMCID: PMC5048406 DOI: 10.1186/s12866-016-0855-8] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 09/28/2016] [Indexed: 12/18/2022] Open
Abstract
Background Staphylococcus aureus is the principle causative pathogen of osteomyelitis and implant-associated bone infections. It is able to invade and to proliferate inside osteoblasts thus avoiding antibiotic therapy and the host immune system. Therefore, development of alternative approaches to stimulate host innate immune responses could be beneficial in prophylaxis against S. aureus infection. TLR9 is the intracellular receptor which recognizes unmethylated bacterial CpG-DNA and activates immune cells. Synthetic CpG-motifs containing oligodeoxynucleotide (CpG-ODNs) mimics the stimulatory effect of bacterial DNA. Results Osteoblast-like SAOS-2 cells were pretreated with CpG-ODN type-A 2216, type-B 2006, or negative CpG-ODN 2243 (negative control) 4 h before infection with S. aureus isolate EDCC 5055 (=DSM 28763). Intracellular bacteria were streaked on BHI plates 4 h and 20 h after infection. ODN2216 as well as ODN2006 but not ODN2243 were able to significantly inhibit the intracellular bacterial growth because about 31 % as well as 43 % of intracellular S. aureus could survive the pretreatment of SAOS-2 cells with ODN2216 or ODN2006 respectively 4 h and 20 h post-infection. RT-PCR analysis of cDNAs from SAOS-2 cells showed that pretreatment with ODN2216 or ODN2006 stimulated the expression of TLR9. Pretreatment of SAOS-2 cells with ODN2216 or ODN2006 but not ODN2243 managed to induce reactive oxygen species (ROS) production inside osteoblasts as measured by flow cytometry analysis. Moreover, treating SAOS-2 cells with the antioxidant Diphenyleneiodonium (DPI) obviously reduced S. aureus killing ability of TLR9 agonists mediated by oxidative stress. Conclusions In this work we demonstrated for the first time that CPG-ODNs have inhibitory effects on S. aureus survival inside SAOS-2 osteoblast-like cell line. This effect was attributed to stimulation of TLR9 and subsequent induction of oxidative stress. Pretreatment of infected SAOS-2 cells with ROS inhibitors resulted in the abolishment of the CPG-ODNs killing effects.
Collapse
Affiliation(s)
- Walid Mohamed
- Laboratory of Experimental Trauma Surgery Giessen, Justus-Liebig-University Giessen, 35394, Giessen, Germany. .,Institute of Medical Microbiology, German Centre of Infection Research, Justus-Liebig-University Giessen, 35392, Giessen, Germany.
| | - Eugen Domann
- Institute of Medical Microbiology, German Centre of Infection Research, Justus-Liebig-University Giessen, 35392, Giessen, Germany
| | - Trinad Chakraborty
- Institute of Medical Microbiology, German Centre of Infection Research, Justus-Liebig-University Giessen, 35392, Giessen, Germany
| | - Gopala Mannala
- Laboratory of Experimental Trauma Surgery Giessen, Justus-Liebig-University Giessen, 35394, Giessen, Germany
| | - Katrin S Lips
- Laboratory of Experimental Trauma Surgery Giessen, Justus-Liebig-University Giessen, 35394, Giessen, Germany
| | - Christian Heiss
- Laboratory of Experimental Trauma Surgery Giessen, Justus-Liebig-University Giessen, 35394, Giessen, Germany.,Department of Trauma Surgery Giessen, Justus-Liebig-University Giessen, 35385, Giessen, Germany
| | - Reinhard Schnettler
- Laboratory of Experimental Trauma Surgery Giessen, Justus-Liebig-University Giessen, 35394, Giessen, Germany.,Department of Trauma Surgery Giessen, Justus-Liebig-University Giessen, 35385, Giessen, Germany
| | - Volker Alt
- Laboratory of Experimental Trauma Surgery Giessen, Justus-Liebig-University Giessen, 35394, Giessen, Germany.,Department of Trauma Surgery Giessen, Justus-Liebig-University Giessen, 35385, Giessen, Germany
| |
Collapse
|
31
|
Kitahata Y, Kanuma T, Hayashi M, Kobayashi N, Ozasa K, Kusakabe T, Temizoz B, Kuroda E, Yamaue H, Coban C, Yamamoto T, Kobiyama K, Aoshi T, Ishii KJ. Circulating nano-particulate TLR9 agonist scouts out tumor microenvironment to release immunogenic dead tumor cells. Oncotarget 2016; 7:48860-48869. [PMID: 27384490 PMCID: PMC5226476 DOI: 10.18632/oncotarget.10379] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 06/18/2016] [Indexed: 12/26/2022] Open
Abstract
Recent evidence suggest that a β-glucan derived from mushroom Schizophyllan(SPG) complexed with a humanized TLR9 agonistic CpG DNA, K3 (K3-SPG) is a promising vaccine adjuvant that induces robust CD8 T cell responses to co-administered antigen. However, it has not been investigated whether K3-SPG alone can act as an anti-cancer immunotherapeutic agent or not. Here, we demonstrate that intravenous injection of K3-SPG, but not CpG alone, is accumulated in the tumor microenvironment and triggered immunogenic cell death (ICD) of tumor cells by local induction of type-I interferon (IFN) as well as IL-12. Resultant innate immune activation as well as subsequent tumor-specific CD8 T cell responses were contributed the tumor growth suppression. This anti-tumor effect of K3-SPG monotherapy was also confirmed by using various tumor models including pancreatic cancer peritoneal dissemination model. Taken together, nano-particulate TLR9 agonist injected intravenously can scout out tumor microenvironment to provoke local innate immune activation and release dead tumor cells into circulation that may induce broader and protective tumor antigen-specific CD8 T cells.
Collapse
Affiliation(s)
- Yuji Kitahata
- Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan
- 2nd Department of Surgery, Wakayama Medical University, Wakayama, Japan
| | - Tomohiro Kanuma
- Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan
- Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan
| | - Masayuki Hayashi
- Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan
| | - Nobuyoshi Kobayashi
- Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan
| | - Koji Ozasa
- Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan
- Department of Pediatrics, Yokohama City University, Yokohama, Japan
| | - Takato Kusakabe
- Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan
- Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan
| | - Burcu Temizoz
- Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan
| | - Etsushi Kuroda
- Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan
| | - Hiroki Yamaue
- 2nd Department of Surgery, Wakayama Medical University, Wakayama, Japan
| | - Cevayir Coban
- Laboratory of Malaria Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Takuya Yamamoto
- Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan
- Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan
| | - Kouji Kobiyama
- Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan
- Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan
| | - Taiki Aoshi
- Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan
- Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan
| | - Ken J. Ishii
- Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan
- Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan
| |
Collapse
|
32
|
Pyzer AR, Cole L, Rosenblatt J, Avigan DE. Myeloid-derived suppressor cells as effectors of immune suppression in cancer. Int J Cancer 2016; 139:1915-26. [PMID: 27299510 DOI: 10.1002/ijc.30232] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 06/07/2016] [Accepted: 06/08/2016] [Indexed: 12/11/2022]
Abstract
The tumor microenvironment consists of an immunosuppressive niche created by the complex interactions between cancer cells and surrounding stromal cells. A critical component of this environment are myeloid-derived suppressor cells (MDSCs), a heterogeneous group of immature myeloid cells arrested at different stages of differentiation and expanded in response to a variety of tumor factors. MDSCs exert diverse effects in modulating the interactions between immune effector cells and the malignant cells. An increased presence of MDSCs is associated with tumor progression, poorer outcomes, and decreased effectiveness of immunotherapeutic strategies. In this article, we will review our current understanding of the mechanisms that underlie MDSC expansion and their immune-suppressive function. Finally, we review the preclinical studies and clinical trials that have attempted to target MDSCs, in order to improve responses to cancer therapies.
Collapse
Affiliation(s)
- Athalia Rachel Pyzer
- Bone Marrow Transplant, Beth Israel Deaconess Medical Center, Center for Life Sciences, CLS724, Boston, MA
| | - Leandra Cole
- Bone Marrow Transplant, Beth Israel Deaconess Medical Center, Center for Life Sciences, CLS724, Boston, MA
| | - Jacalyn Rosenblatt
- Bone Marrow Transplant, Beth Israel Deaconess Medical Center, Center for Life Sciences, CLS724, Boston, MA
| | - David E Avigan
- Bone Marrow Transplant, Beth Israel Deaconess Medical Center, Center for Life Sciences, CLS724, Boston, MA
| |
Collapse
|
33
|
Jang JK, Khawli LA, Canter DC, Hu P, Zhu TH, Wu BW, Angell TE, Li Z, Epstein AL. Systemic delivery of chTNT-3/CpG immunoconjugates for immunotherapy in murine solid tumor models. Cancer Immunol Immunother 2016; 65:511-23. [PMID: 26960932 DOI: 10.1007/s00262-016-1813-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 02/19/2016] [Indexed: 12/25/2022]
Abstract
CpG oligodeoxynucleotides (CpG) potently activate the immune system by mimicking microbial DNA. Conjugation of CpG to chTNT-3, an antibody targeting the necrotic centers of tumors, enabled CpG to accumulate in tumors after systemic delivery, where it can activate the immune system in the presence of tumor antigens. CpG chemically conjugated to chTNT-3 (chTNT-3/CpG) were compared to free CpG in their ability to stimulate the immune system in vitro and reduce tumor burden in vivo. In subcutaneous Colon 26 adenocarcinoma and B16-F10 melanoma models in BALB/c and C57BL/6 mice, respectively, chTNT-3/CpG, free CpG, or several different control constructs were administered systemically. Intraperitoneal injections of chTNT-3/CpG delayed tumor growth and improved survival and were comparable to intratumorally administered CpG. Compared to saline-treated mice, chTNT-3/CpG-treated mice had smaller average tumor volumes by as much as 72% in Colon 26-bearing mice and 79% in B16-bearing mice. Systemically delivered free CpG and CpG conjugated to an isotype control antibody did not reduce tumor burden or improve survival. In this study, chTNT-3/CpG retained immunostimulatory activity of the CpG moiety and enabled delivery to tumors. Because systemically administered CpG rapidly clear the body and do not accumulate into tumors, chTNT-3/CpG provide a solution to the limitations observed in preclinical and clinical trials.
Collapse
Affiliation(s)
- Julie K Jang
- Department of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR 205, Los Angeles, CA, 90033, USA
| | - Leslie A Khawli
- Department of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR 205, Los Angeles, CA, 90033, USA
| | - David C Canter
- Department of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR 205, Los Angeles, CA, 90033, USA
| | - Peisheng Hu
- Department of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR 205, Los Angeles, CA, 90033, USA
| | - Tian H Zhu
- Department of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR 205, Los Angeles, CA, 90033, USA
| | - Brian W Wu
- Department of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR 205, Los Angeles, CA, 90033, USA
| | - Trevor E Angell
- Department of Endocrinology, Metabolism, and Hypertension, Thyroid Section, Brigham and Women's Hospital, Boston, MA, USA
| | - Zhongjun Li
- Department of Blood Transfusion, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Alan L Epstein
- Department of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR 205, Los Angeles, CA, 90033, USA.
| |
Collapse
|
34
|
Behm B, Di Fazio P, Michl P, Neureiter D, Kemmerling R, Hahn EG, Strobel D, Gress T, Schuppan D, Wissniowski TT. Additive antitumour response to the rabbit VX2 hepatoma by combined radio frequency ablation and toll like receptor 9 stimulation. Gut 2016; 65:134-143. [PMID: 25524262 DOI: 10.1136/gutjnl-2014-308286] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Accepted: 11/11/2014] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Radiofrequency ablation (RFA), a palliative therapeutic option for solid hepatic tumours, stimulates localised and systemic antitumour cytotoxic T cells. We studied how far addition of CpG B oligonucleotides, toll like receptor (TLR) 9 agonists, would increase the antitumoural T cell response of RFA in the highly aggressive VX2 hepatoma. METHODS Rabbits were randomised to receive RFA, CpG B, their combination or no therapy. The antitumour efficacy of RFA alone or in combination with CpG B was further tested by rechallenging a separate group with intravenously injected VX2 tumour cells after 120 days. Animals were assessed for survival, tumour size and spread, and tumour and immune related histological markers after 120 days. Peripheral blood mononuclear cells were tested for tumour-specific T cell activation and cytotoxicity. Immune modulatory cytokines tumour necrosis factor α, interleukin (IL)-2/IL-8/IL-10/IL-12 and interferon γ, and vascular endothelial growth factor were measured in serum. RESULTS Mean survival of untreated animals was 36 days, as compared with 97, 78 and 114 days for RFA, CpG and combination therapy, respectively. Compared with untreated controls, antitumour T cell stimulation/cytotoxicity increased 26/16-fold, 32/17-fold and 50/38-fold 2 weeks after RFA, CpG and combination treatments, respectively. The combination inhibited tumour spread to lungs and peritoneum significantly and prohibited new tumour growth in animals receiving a secondary systemic tumour cell injection. RFA alone induced a Th1 cytokine pattern, while IL-8 and IL-10 were only upregulated in CpG treated animals and controls. CONCLUSIONS The combination of TLR9 stimulation with RFA resulted in a potentiated antitumour T cell response and cytotoxicity in the VX2 tumour model. Only this combination prevented subsequent tumour spread and resulted in a significantly improved survival, justifying the need for further exploration of the combination of ablative therapies and TLR9 agonists in liver cancer.
Collapse
Affiliation(s)
- Barbara Behm
- Department of Medicine 1, University Hospital Erlangen-Nuremberg, Erlangen, Germany
| | - Pietro Di Fazio
- Institute for Surgical Research, Philipps-University Marburg, Marburg, Germany
| | - Patrick Michl
- Division of Gastroenterology, University Hospital, Philipps-University Marburg, Marburg, Germany
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University, Salzburg, Austria
| | - Ralf Kemmerling
- Institute of Pathology, Paracelsus Medical University, Salzburg, Austria
| | - Eckhart Georg Hahn
- Department of Medicine 1, University Hospital Erlangen-Nuremberg, Erlangen, Germany
| | - Deike Strobel
- Department of Medicine 1, University Hospital Erlangen-Nuremberg, Erlangen, Germany
| | - Thomas Gress
- Division of Gastroenterology, University Hospital, Philipps-University Marburg, Marburg, Germany
| | - Detlef Schuppan
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA Institute of Translational Immunology, University Medical Center, Mainz, Germany
| | - Thaddaeus Till Wissniowski
- Department of Medicine 1, University Hospital Erlangen-Nuremberg, Erlangen, Germany Division of Gastroenterology, University Hospital, Philipps-University Marburg, Marburg, Germany
| |
Collapse
|
35
|
Jordan M, Waxman DJ. CpG-1826 immunotherapy potentiates chemotherapeutic and anti-tumor immune responses to metronomic cyclophosphamide in a preclinical glioma model. Cancer Lett 2015; 373:88-96. [PMID: 26655275 DOI: 10.1016/j.canlet.2015.11.029] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Revised: 11/26/2015] [Accepted: 11/27/2015] [Indexed: 02/08/2023]
Abstract
Cyclophosphamide administered on an intermittent metronomic schedule induces strong immune-dependent regression in several glioma models. Here we investigate whether this immunogenic chemotherapy can be potentiated by combination with the immune stimulatory TLR9 agonist CpG-1826. CpG-1826 treatment of GL261 gliomas implanted in immune competent mice induced tumor growth delay associated with increased tumor recruitment of macrophages and B cells. Anti-tumor responses varied between individuals, with CpG-1826 inducing robust tumor growth delay in ~50% of treated mice. Both high and low CpG-1826-responsive mice showed striking improvements when CpG-1826 was combined with cyclophosphamide treatment. Tumor-associated macrophages, B cells, dendritic cells, and cytotoxic T cells were increased, T regulatory cells were not induced, and long-term GL261 glioma regression with immune memory was achieved when CpG-1826 was combined with either single cyclophosphamide dosing (90 mg/kg) or metronomic cyclophosphamide treatment (two cycles at 45 mg/kg, spaced 12-days apart). B16F10 melanoma, a low immunogenic tumor model, also showed enhanced immune and anti-tumor responses to cyclophosphamide/CpG-1826 chemoimmunotherapy, but unlike GL261 tumors, did not regress. TLR9-based immunotherapy can thus be effectively combined with immunogenic cyclophosphamide treatment to enhance immune-based anti-tumor responses, even in poorly immunogenic cancer models.
Collapse
Affiliation(s)
- Marie Jordan
- Division of Cell and Molecular Biology, Department of Biology, Boston University, 5 Cummington Mall, Boston, MA 02215, USA
| | - David J Waxman
- Division of Cell and Molecular Biology, Department of Biology, Boston University, 5 Cummington Mall, Boston, MA 02215, USA.
| |
Collapse
|
36
|
Anz D, Rapp M, Eiber S, Koelzer VH, Thaler R, Haubner S, Knott M, Nagel S, Golic M, Wiedemann GM, Bauernfeind F, Wurzenberger C, Hornung V, Scholz C, Mayr D, Rothenfusser S, Endres S, Bourquin C. Suppression of intratumoral CCL22 by type i interferon inhibits migration of regulatory T cells and blocks cancer progression. Cancer Res 2015; 75:4483-93. [PMID: 26432403 DOI: 10.1158/0008-5472.can-14-3499] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 08/06/2015] [Indexed: 11/16/2022]
Abstract
The chemokine CCL22 is abundantly expressed in many types of cancer and is instrumental for intratumoral recruitment of regulatory T cells (Treg), an important subset of immunosuppressive and tumor-promoting lymphocytes. In this study, we offer evidence for a generalized strategy to blunt Treg activity that can limit immune escape and promote tumor rejection. Activation of innate immunity with Toll-like receptor (TLR) or RIG-I-like receptor (RLR) ligands prevented accumulation of Treg in tumors by blocking their immigration. Mechanistic investigations indicated that Treg blockade was a consequence of reduced intratumoral CCL22 levels caused by type I IFN. Notably, stable expression of CCL22 abrogated the antitumor effects of treatment with RLR or TLR ligands. Taken together, our findings argue that type I IFN blocks the Treg-attracting chemokine CCL22 and thus helps limit the recruitment of Treg to tumors, a finding with implications for cancer immunotherapy.
Collapse
Affiliation(s)
- David Anz
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany. Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Moritz Rapp
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Stephan Eiber
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany. Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Viktor H Koelzer
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Raffael Thaler
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Sascha Haubner
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Max Knott
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Sarah Nagel
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Michaela Golic
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Gabriela M Wiedemann
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Franz Bauernfeind
- Institute of Molecular Medicine, Universitätsklinikum Bonn, Bonn, Germany
| | - Cornelia Wurzenberger
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Veit Hornung
- Institute of Molecular Medicine, Universitätsklinikum Bonn, Bonn, Germany. Institute of Molecular Medicine, Universitätsklinikum Bonn, Bonn, Germany
| | - Christoph Scholz
- Department of Obstetrics and Gynecology, Ulm University Medical Centre, Ulm, Germany
| | - Doris Mayr
- Department of Pathology, Ludwig-Maximilians-Universität, Munich, Germany
| | - Simon Rothenfusser
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Stefan Endres
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany.
| | - Carole Bourquin
- Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany. Department of Medicine, University of Fribourg, Fribourg, Switzerland
| |
Collapse
|
37
|
Sato T, Shimosato T, Ueda A, Ishigatsubo Y, Klinman DM. Intrapulmonary Delivery of CpG Microparticles Eliminates Lung Tumors. Mol Cancer Ther 2015. [PMID: 26206336 DOI: 10.1158/1535-7163.mct-15-0401] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
CpG oligonucleotides (ODN) stimulate the innate immune system by triggering cells that express TLR9. The resulting response promotes tumor regression, an effect optimized by delivery of CpG ODN to the tumor site. This work examines the effect of instilling CpG ODN adsorbed onto polyketal microparticles (CpG-MP) into the lungs of mice with non-small cell lung cancer. Intrapulmonary delivery of CpG-MP improved ODN uptake and retention at the tumor site, thereby inducing a stronger Th1 response than systemically administered or unadsorbed CpG ODN. CpG-MP reversed the immunosuppression that characterized the tumor microenvironment by (i) decreasing the number of immunosuppressive Tregs and M2 macrophages while (ii) increasing the number of tumoricidal CD8(+) T cells and M1 macrophages. These effects promoted tumor regression and culminated in 82% permanent survival of mice with otherwise fatal Lewis lung cancer.
Collapse
Affiliation(s)
- Takashi Sato
- Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland. Graduate School of Internal Medicine and Clinical Immunology, Yokohama City University, Yokohama, Japan
| | | | - Atsuhisa Ueda
- Graduate School of Internal Medicine and Clinical Immunology, Yokohama City University, Yokohama, Japan
| | - Yoshiaki Ishigatsubo
- Graduate School of Internal Medicine and Clinical Immunology, Yokohama City University, Yokohama, Japan
| | - Dennis M Klinman
- Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland.
| |
Collapse
|
38
|
Stern C, Kasnitz N, Kocijancic D, Trittel S, Riese P, Guzman CA, Leschner S, Weiss S. Induction of CD4(+) and CD8(+) anti-tumor effector T cell responses by bacteria mediated tumor therapy. Int J Cancer 2015; 137:2019-28. [PMID: 25868911 DOI: 10.1002/ijc.29567] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Revised: 02/05/2015] [Accepted: 03/11/2015] [Indexed: 01/30/2023]
Abstract
Facultative anaerobic bacteria like E. coli can colonize solid tumors often resulting in tumor growth retardation or even clearance. Little mechanistic knowledge is available for this phenomenon which is however crucial for optimization and further implementation in the clinic. Here, we show that intravenous injections with E. coli TOP10 can induce clearance of CT26 tumors in BALB/c mice. Importantly, re-challenging mice which had cleared tumors showed that clearance was due to a specific immune reaction. Accordingly, lymphopenic mice never showed tumor clearance after infection. Depletion experiments revealed that during induction phase, CD8(+) T cells are the sole effectors responsible for tumor clearance while in the memory phase CD8(+) and CD4(+) T cells were involved. This was confirmed by adoptive transfer. CD4(+) and CD8(+) T cells could reject newly set tumors while CD8(+) T cells could even reject established tumors. Detailed analysis of adoptively transferred CD4(+) T cells during tumor challenge revealed expression of granzyme B, FasL, TNF-α and IFN-γ in such T cells that might be involved in the anti-tumor activity. Our findings should pave the way for further optimization steps of this promising therapy.
Collapse
Affiliation(s)
- Christian Stern
- Department of Molecular Immunology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Nadine Kasnitz
- Department of Molecular Immunology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Dino Kocijancic
- Department of Molecular Immunology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Stephanie Trittel
- Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Peggy Riese
- Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Carlos A Guzman
- Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Sara Leschner
- Department of Molecular Immunology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Siegfried Weiss
- Department of Molecular Immunology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| |
Collapse
|
39
|
Shirota H, Tross D, Klinman DM. CpG Oligonucleotides as Cancer Vaccine Adjuvants. Vaccines (Basel) 2015; 3:390-407. [PMID: 26343193 PMCID: PMC4494345 DOI: 10.3390/vaccines3020390] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 04/23/2015] [Accepted: 04/28/2015] [Indexed: 12/16/2022] Open
Abstract
Adjuvants improve host responsiveness to co-delivered vaccines through a variety of mechanisms. Agents that trigger cells expressing Toll-like receptors (TLR) activate an innate immune response that enhances the induction of vaccine-specific immunity. When administered in combination with vaccines designed to prevent or slow tumor growth, TLR agonists have significantly improved the generation of cytotoxic T lymphocytes. Unfortunately, vaccines containing TLR agonists have rarely been able to eliminate large established tumors when administered systemically. To improve efficacy, attention has focused on delivering TLR agonists intra-tumorally with the intent of altering the tumor microenvironment. Agonists targeting TLRs 7/8 or 9 can reduce the frequency of Tregs while causing immunosuppressive MDSC in the tumor bed to differentiate into tumoricidal macrophages thereby enhancing tumor elimination. This work reviews pre-clinical and clinical studies concerning the utility of TLR 7/8/9 agonists as adjuvants for tumor vaccines.
Collapse
Affiliation(s)
- Hidekazu Shirota
- Department of Clinical Oncology, Tohoku University Hospital, Sendai 980-8577, Japan.
| | - Debra Tross
- Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA.
| | - Dennis M Klinman
- Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA.
| |
Collapse
|
40
|
Ito H, Ando T, Arioka Y, Saito K, Seishima M. Inhibition of indoleamine 2,3-dioxygenase activity enhances the anti-tumour effects of a Toll-like receptor 7 agonist in an established cancer model. Immunology 2015; 144:621-30. [PMID: 25322876 DOI: 10.1111/imm.12413] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Revised: 10/02/2014] [Accepted: 10/14/2014] [Indexed: 12/12/2022] Open
Abstract
Toll-like receptor (TLR) agonists have been shown to have anti-tumour activity in basic research and clinical studies. However, TLR agonist monotherapy does not sufficiently eliminate tumours. Activation of the innate immune response by TLR agonists is effective at driving adaptive immunity via interleukin-12 (IL-12) or IL-1, but is counteracted by the simultaneous induction of immunosuppressive cytokines and other molecules, including IL-10, transforming growth factor-β, and indoleamine 2,3-dioxygenase (IDO). In the present study, we evaluated the anti-cancer effect of the TLR7 agonist, imiquimod (IMQ), in the absence of IDO activity. The administration of IMQ in IDO knockout (KO) mice inoculated with tumour cells significantly suppressed tumour progression compared with that in wild-type (WT) mice, and improved the survival rate. Moreover, injection with IMQ enhanced the tumour antigen-specific T helper type 1 response in IDO-KO mice with tumours. Combination therapy with IMQ and an IDO inhibitor also significantly inhibited tumour growth. Our results indicated that the enhancement of IDO expression with TLR agonists in cancer treatment might impair host anti-tumour immunity while the inhibition of IDO could enhance the therapeutic efficacy of TLR agonists via the increase of T helper type 1 immune response.
Collapse
Affiliation(s)
- Hiroyasu Ito
- Department of Informative Clinical Medicine, First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | | | | | | | | |
Collapse
|
41
|
Draghiciu O, Lubbers J, Nijman HW, Daemen T. Myeloid derived suppressor cells-An overview of combat strategies to increase immunotherapy efficacy. Oncoimmunology 2015; 4:e954829. [PMID: 25949858 PMCID: PMC4368153 DOI: 10.4161/21624011.2014.954829] [Citation(s) in RCA: 217] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Accepted: 07/07/2014] [Indexed: 01/08/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) contribute to tumor-mediated immune escape and negatively correlate with overall survival of cancer patients. Nowadays, a variety of methods to target MDSCs are being investigated. Based on the intervention stage of MDSCs, namely development, expansion and activation, function and turnover, these methods can be divided into: (I) prevention or differentiation to mature cells, (II) blockade of MDSC expansion and activation, (III) inhibition of MDSC suppressive activity or (IV) depletion of intratumoral MDSCs. This review describes effective mono- or multimodal-therapies that target MDSCs for the benefit of cancer treatment.
Collapse
Key Words
- 5-FU, 5-fluorouracil
- 5-Fluorouracil
- ADAM17, metalloproteinase domain-containing protein 17
- APCs, antigen presenting cells
- ARG1, arginase-1
- ATRA, all-trans retinoic acid
- CCL2, chemokine (C-C motif) ligand 2
- CD62L, L-selectin
- CDDO-Me, bardoxolone methyl
- COX2, cyclooxygenase 2
- CTLs, cytotoxic T lymphocytes
- CXCL12, chemokine (C-X-C motif) ligand 12
- CXCL15, chemokine (C-X-C motif) ligand 15
- DCs, dendritic cells
- ERK1/2, extracellular signal-regulated kinases
- Flt3, Fms-like tyrosine kinase 3
- FoxP3, forkhead box P3
- GITR, anti-glucocorticoid tumor necrosis factor receptor
- GM-CSF/CSF2, granulocyte monocyte colony stimulating factor
- GSH, glutathione
- HIF-1α, hypoxia inducible factor 1α
- HLA, human leukocyte antigen
- HNSCC, head and neck squamous cell carcinoma
- HPV-16, human papillomavirus 16
- HSCs, hematopoietic stem cells
- ICT, 3, 5, 7-trihydroxy-4′-emthoxy-8-(3-hydroxy-3-methylbutyl)-flavone
- IFNγ, interferon γ
- IL-10, interleukin 10
- IL-13, interleukin 13
- IL-1β, interleukin 1 β
- IL-4, interleukin 4
- IL-6, interleukin 6
- IMCs, immature myeloid cells
- JAK2, Janus kinase 2
- MDSCs, myeloid-derived suppressor cells
- MMPs, metalloproteinases (e.g., MMP9)
- Myd88, myeloid differentiation primary response protein 88
- NAC, N-acetyl cysteine
- NADPH, nicotinamide adenine dinucleotide phosphate-oxidase NK cells, natural killer cells
- NO, nitric oxide
- NOHA, N-hydroxy-L-Arginine
- NSAID, nonsteroidal anti-inflammatory drugs
- ODN, oligodeoxynucleotides
- PDE-5, phosphodiesterase type 5
- PGE2, prostaglandin E2
- RNS, reactive nitrogen species
- ROS, reactive oxygen species
- SCF, stem cell factor
- STAT3, signal transducer and activator of transcription 3
- TAMs, tumor-associated macrophages
- TCR, T cell receptor
- TGFβ, transforming growth factor β
- TNFα, tumor necrosis factor α
- Tregs, regulatory T cells
- VEGFR, vascular endothelial growth factor receptor
- WA, withaferin A
- WRE, Withaferin somnifera
- all-trans retinoic acid
- bisphosphonates
- c-kit, Mast/stem cell growth factor receptor
- gemcitabine
- iNOS2, inducible nitric oxid synthase 2
- immune suppressive mechanisms
- mRCC, metastatic renal cell carcinoma
- myeloid-derived suppressor cells
- sunitinib therapeutic vaccination
Collapse
Affiliation(s)
- Oana Draghiciu
- Department of Medical Microbiology; Tumor Virology and Cancer Immunotherapy; University of Groningen; University Medical Center Groningen ; Groningen, The Netherlands
| | - Joyce Lubbers
- Department of Medical Microbiology; Tumor Virology and Cancer Immunotherapy; University of Groningen; University Medical Center Groningen ; Groningen, The Netherlands
| | - Hans W Nijman
- Department of Gynecology; University of Groningen; University Medical Center Groningen ; Groningen, The Netherlands
| | - Toos Daemen
- Department of Medical Microbiology; Tumor Virology and Cancer Immunotherapy; University of Groningen; University Medical Center Groningen ; Groningen, The Netherlands
| |
Collapse
|
42
|
Waldron TJ, Quatromoni JG, Karakasheva TA, Singhal S, Rustgi AK. Myeloid derived suppressor cells: Targets for therapy. Oncoimmunology 2014; 2:e24117. [PMID: 23734336 PMCID: PMC3654606 DOI: 10.4161/onci.24117] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Revised: 02/22/2013] [Accepted: 02/26/2013] [Indexed: 01/14/2023] Open
Abstract
The goal of achieving measurable response with cancer immunotherapy requires counteracting the immunosuppressive characteristics of tumors. One of the mechanisms that tumors utilize to escape immunosurveillance is the activation of myeloid derived suppressor cells (MDSCs). Upon activation by tumor-derived signals, MDSCs inhibit the ability of the host to mount an anti-tumor immune response via their capacity to suppress both the innate and adaptive immune systems. Despite their relatively recent discovery and characterization, anti-MDSC agents have been identified, which may improve immunotherapy efficacy.
Collapse
Affiliation(s)
- Todd J Waldron
- Gastroenterology Division; Department of Medicine; University of Pennsylvania; Philadelphia, PA USA ; Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA
| | | | | | | | | |
Collapse
|
43
|
Zhao BG, Vasilakos JP, Tross D, Smirnov D, Klinman DM. Combination therapy targeting toll like receptors 7, 8 and 9 eliminates large established tumors. J Immunother Cancer 2014; 2:12. [PMID: 24982761 PMCID: PMC4075973 DOI: 10.1186/2051-1426-2-12] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Accepted: 04/01/2014] [Indexed: 12/14/2022] Open
Abstract
Background The TLR7/8 agonist 3M-052 and the TLR9 agonist CpG ODN both trigger innate immune responses that support the induction of tumor-specific immunity. Previous studies showed that these agonists used individually could improve the survival of mice challenged with small tumors but were of limited therapeutic benefit against large/advanced tumors. Methods Normal mice were challenged with syngeneic tumors. Once these tumors reached clinically detectable size (500–800 mm3) they were treated by intra-tumoral injection with 3M-052 and/or CpG ODN. Anti-tumor immunity and tumor growth were evaluated. Results The co-delivery of agonists targeting TLRs 7, 8 and 9 increased the number and tumoricidal activity of tumor infiltrating CTL and NK cells while reducing the frequency of immunosuppressive MDSC. The combination of 3M-052 plus CpG ODN (but not each agent alone) eradicated large primary tumors and established long-term protective immunity. Conclusion The combination of agonists targeting TLRs 7/8 and 9 represents a significant improvement in cancer immunotherapy.
Collapse
Affiliation(s)
- By Gan Zhao
- Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick MD 21702, USA
| | | | - Debra Tross
- Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick MD 21702, USA
| | - Dmitri Smirnov
- 3M Drug Delivery Systems Division, St. Paul MN 55144, USA
| | - Dennis M Klinman
- Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick MD 21702, USA
| |
Collapse
|
44
|
Shirota H, Klinman DM. Use of CpG oligonucleotides for cancer immunotherapy and their effect on immunity in the tumor microenvironment. Immunotherapy 2014; 5:787-9. [PMID: 23902544 DOI: 10.2217/imt.13.70] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
|
45
|
Ilyinskii PO, Roy CJ, O'Neil CP, Browning EA, Pittet LA, Altreuter DH, Alexis F, Tonti E, Shi J, Basto PA, Iannacone M, Radovic-Moreno AF, Langer RS, Farokhzad OC, von Andrian UH, Johnston LPM, Kishimoto TK. Adjuvant-carrying synthetic vaccine particles augment the immune response to encapsulated antigen and exhibit strong local immune activation without inducing systemic cytokine release. Vaccine 2014; 32:2882-95. [PMID: 24593999 PMCID: PMC4059049 DOI: 10.1016/j.vaccine.2014.02.027] [Citation(s) in RCA: 127] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Augmentation of immunogenicity can be achieved by particulate delivery of an antigen and by its co-administration with an adjuvant. However, many adjuvants initiate strong systemic inflammatory reactions in vivo, leading to potential adverse events and safety concerns. We have developed a synthetic vaccine particle (SVP) technology that enables co-encapsulation of antigen with potent adjuvants. We demonstrate that co-delivery of an antigen with a TLR7/8 or TLR9 agonist in synthetic polymer nanoparticles results in a strong augmentation of humoral and cellular immune responses with minimal systemic production of inflammatory cytokines. In contrast, antigen encapsulated into nanoparticles and admixed with free TLR7/8 agonist leads to lower immunogenicity and rapid induction of high levels of inflammatory cytokines in the serum (e.g., TNF-α and IL-6 levels are 50- to 200-fold higher upon injection of free resiquimod (R848) than of nanoparticle-encapsulated R848). Conversely, local immune stimulation as evidenced by cellular infiltration of draining lymph nodes and by intranodal cytokine production was more pronounced and persisted longer when SVP-encapsulated TLR agonists were used. The strong local immune activation achieved using a modular self-assembling nanoparticle platform markedly enhanced immunogenicity and was equally effective whether antigen and adjuvant were co-encapsulated in a single nanoparticle formulation or co-delivered in two separate nanoparticles. Moreover, particle encapsulation enabled the utilization of CpG oligonucleotides with the natural phosphodiester backbone, which are otherwise rapidly hydrolyzed by nucleases in vivo. The use of SVP may enable clinical use of potent TLR agonists as vaccine adjuvants for indications where cellular immunity or robust humoral responses are required.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Frank Alexis
- Laboratory of Nanomedicine and Biomaterials, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Elena Tonti
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA
| | - Jinjun Shi
- Laboratory of Nanomedicine and Biomaterials, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Pamela A Basto
- David H. Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA
| | - Matteo Iannacone
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA
| | - Aleksandar F Radovic-Moreno
- David H. Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA
| | - Robert S Langer
- David H. Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA
| | - Omid C Farokhzad
- Laboratory of Nanomedicine and Biomaterials, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Ulrich H von Andrian
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA
| | | | | |
Collapse
|
46
|
Rapp M, Anz D, Schnurr M. Isolation of intratumoral leukocytes of TLR-stimulated tumor-bearing mice. Methods Mol Biol 2014; 1169:175-9. [PMID: 24957239 DOI: 10.1007/978-1-4939-0882-0_16] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Toll-like receptor (TLR) ligands hold promise for cancer immunotherapy. The isolation of intratumoral leukocytes of tumor-bearing mice is a useful technique for analyzing the immunological effects of TLR ligands on the tumor microenvironment. These isolated immune cells can be directly used for analysis (e.g., by flow cytometry) or cultured for functional in vitro studies. Here, we describe the isolation of intratumoral leukocytes by density gradient centrifugation. This technique can be used to isolate leukocytes from freshly dissected murine tumors.
Collapse
Affiliation(s)
- Moritz Rapp
- Division of Clinical Pharmacology, Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, Ziemsenstr.1, D-80336, Munich, Germany
| | | | | |
Collapse
|
47
|
Thomas SN, Vokali E, Lund AW, Hubbell JA, Swartz MA. Targeting the tumor-draining lymph node with adjuvanted nanoparticles reshapes the anti-tumor immune response. Biomaterials 2013; 35:814-24. [PMID: 24144906 DOI: 10.1016/j.biomaterials.2013.10.003] [Citation(s) in RCA: 234] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Accepted: 10/01/2013] [Indexed: 12/30/2022]
Abstract
Accumulating evidence implicates the tumor-draining lymph node (TDLN) in tumor-induced immune escape, as it drains regulatory molecules and leukocytes from the tumor microenvironment. We asked whether targeted delivery of adjuvant to the TDLN, presumably already bathed in tumor antigens, could promote anti-tumor immunity and hinder tumor growth. To this end, we used 30 nm polymeric nanoparticles (NPs) that effectively target dendritic cells (DCs, CD11c(+)) within the lymph node (LN) after intradermal administration. These NPs accumulated within the TDLN when administered in the limb ipsilateral (i.l.) to the tumor or in the non-TDLN when administered in the contralateral (c.l.) limb. Incorporating the adjuvants CpG or paclitaxel into the NPs (CpG-NP and PXL-NP) induced DC maturation in vitro. When administered daily i.l. and thus targeting the TDLN of a B16-F10 melanoma, adjuvanted NPs induced DC maturation within the TDLN and reshaped the CD4(+) T cell distribution within the tumor towards a Th1 (CXCR3(+)) phenotype. Importantly, this also led to an increase in the frequency of antigen-specific CD8(+) T cells within the tumor. This correlated with slowed tumor growth, in contrast to unhindered tumor growth after c.l. delivery of adjuvanted NPs (targeting a non-TDLN) or i.l. delivery of free adjuvant. CpG-NP treatment in the i.l. limb also was associated with an increase in CD8(+)/CD4(+) T cell ratios and frequencies of activated (CD25(+)) CD8(+) T cells within the TDLN whereas PXL-NP treatment reduced the frequency of regulatory T (FoxP3(+) CD4(+)) cells in the TDLN. Together, these data implicate the TDLN as a delivery target for adjuvant therapy of solid tumors.
Collapse
Affiliation(s)
- Susan N Thomas
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH-1015, Switzerland; Swiss Institute for Experimental Cancer Research (ISREC), École Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH-1015, Switzerland
| | | | | | | | | |
Collapse
|
48
|
The Yin and Yang of Toll-like receptors in cancer. Oncogene 2013; 33:3485-95. [PMID: 23934186 DOI: 10.1038/onc.2013.302] [Citation(s) in RCA: 237] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Accepted: 06/10/2013] [Indexed: 02/08/2023]
Abstract
Recognition of non-self molecular patterns by pattern recognition receptors is a cornerstone of innate immunity. Toll-like receptors (TLRs) exert a key role in recognizing pathogen-associated molecular patterns (PAMPs) but have also been implicated in the recognition of damage-associated molecular patterns (DAMPs). As such, TLRs regulate a wide range of biological responses including inflammatory and immune responses during carcinogenesis. The high expression of TLRs by antigen-presenting cells, including dendritic cells, and their ability to induce antitumor mediators such as type I interferon has led to efforts to utilize TLR agonists in tumor therapy in order to convert the often tolerant immune response toward antitumor responses. However, TLRs are also increasingly recognized as regulators of tumor-promoting inflammation and promoters of tumor survival signals. Here, we will review in detail the dichotomous role of TLRs in tumor biology, focusing on relevant TLR-dependent pro- and antitumor pathways, and discuss clinical applications of TLR-targeted therapies for tumor prevention and treatment.
Collapse
|
49
|
Wang X, Wang L, Wan M, Wu X, Yu Y, Wang L. Fully phosphorothioate-modified CpG ODN with PolyG motif inhibits the adhesion of B16 melanoma cells in vitro and tumorigenesis in vivo. Nucleic Acid Ther 2013; 23:253-63. [PMID: 23848522 PMCID: PMC3723239 DOI: 10.1089/nat.2013.0419] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2013] [Accepted: 05/30/2013] [Indexed: 01/20/2023] Open
Abstract
Adhesion to the extracellular matrix and endothelial lining of blood vessels is critical for tumor cells to grow at original or metastatic sites. Inhibition of tumor cell adhesion can be an antitumor strategy. Guanosine-rich (G-rich) oligodeoxynucleotides (ODNs) can inhibit the adhesion of certain tumor cells. However, no data exist on how inclusion of the CpG motif in the G-rich sequence influences tumor cell adhesion and subsequent tumorigenesis. In this study, in vitro and in vivo assays were used to evaluate how a panel of ODN-containing contiguous guanosines and the CpG motif influenced adhesion of B16 melanoma cells. The results showed that a self-designed ODN, named BW001, containing the polyG motif and a full phosphorothioate modification backbone could inhibit B16 melanoma cell adhesion on a culture plate or on a plate coated with various substances. In vivo data revealed that B16 melanoma cells co-administered with BW001 and intraperitoneally injected into mice formed fewer tumor colonies in peritoneal cavities. This effect was related to the polyG motif and the full phosphorothioate modification backbone and enhanced by the existence of the CpG motif. Additional in vivo data showed that survival of tumor-bearing mice in the BW001 group was significantly prolonged, subcutaneous melanoma developed much more slowly, and lung dissemination colonies formed much less often than in mice inoculated with B16 melanoma cells only. The effect was CpG motif-dependent. These results suggest that BW001 may exert an integrated antitumor effect.
Collapse
Affiliation(s)
- Xueju Wang
- Department of Molecular Biology, Norman Bethune College of Medicine, Jilin University, Changchun, China
- Department of Pathology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Liying Wang
- Department of Molecular Biology, Norman Bethune College of Medicine, Jilin University, Changchun, China
- Department of Pathology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Min Wan
- Department of Molecular Biology, Norman Bethune College of Medicine, Jilin University, Changchun, China
| | - Xiuli Wu
- Department of Molecular Biology, Norman Bethune College of Medicine, Jilin University, Changchun, China
| | - Yongli Yu
- Department of Immunology, Norman Bethune College of Medicine, Jilin University, Changchun, China
| | - Liping Wang
- Department of Pathology, China-Japan Union Hospital of Jilin University, Changchun, China
| |
Collapse
|
50
|
Zhuang X, Qiao T, Yuan S, Chen W, Zha L, Yan L. Dose-effect relationship of CpG oligodeoxyribonucleotide 1826 in murine Lewis lung cancer treated with irradiation. Onco Targets Ther 2013; 6:549-54. [PMID: 23723711 PMCID: PMC3666880 DOI: 10.2147/ott.s42485] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Background Cytosine-phosphate-guanine (CpG) oligodeoxyribonucleotides (ODNs), which induce signaling via Toll-like receptor 9, have recently been suggested to enhance sensitivity to traditional therapies, including chemotherapy, in certain cancer cell lines. This study aimed to define the dose-effect relationship for CpG ODN 1826 in increasing radiosensitivity and its impact on immune function in a mouse model of Lewis lung cancer. Methods The tumor-bearing mouse model was induced by injecting Lewis lung cancer cells into the right anterior leg subcutaneously. Sixty-four C57BL/6 J mice were evenly randomized into eight groups, comprising: a control group; an irradiation group; a CpG ODN 0.15 group; a CpG ODN 0.3 group; a CpG ODN 0.45 group; a CpG 0.15 + irradiation group; a CpG 0.3 + irradiation group; and a CpG 0.45 + irradiation group. Tumor growth, serum tumor necrosis factor-alpha and interleukin-12 concentrations, spleen and thymus exponents, and effect of CpG on the secondary immune response were measured, and apoptosis of tumor cells was investigated using TdT-mediated dUTP nick end labeling (TUNEL) after treatment. Results Tumor volumes in the treated groups were smaller than in the control group, with those of the CpG 0.45 + irradiation group being the smallest. TUNEL showed that the apoptosis rate in all the active treatment groups was higher than in the control group. CpG ODN apoptosis rate, serum tumor necrosis factor-alpha and interleukin-12 levels, and the spleen and thymus exponent showed greater improvement in the groups receiving combination therapy of CpG ODN and irradiation than the control group or the group receiving irradiation alone. With the increasing concentration of CpG ODN 1826, its effect became more and more significant, meanwhile, inoculation of Lewis lung cancer cells failed in those CpG ODN-cured mice. Conclusion CpG ODNs dramatically increased the radiosensitivity of Lewis lung cancer and enhanced immune function in mice in a dose-related manner.
Collapse
Affiliation(s)
- Xibing Zhuang
- Department of Oncology, Jinshan Hospital, Medical Center of Fudan University, Shanghai, People's Republic of China
| | | | | | | | | | | |
Collapse
|