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Kwart D, He J, Srivatsan S, Lett C, Golubov J, Oswald EM, Poon P, Ye X, Waite J, Zaretsky AG, Haxhinasto S, Au-Yeung E, Gupta NT, Chiu J, Adler C, Cherravuru S, Malahias E, Negron N, Lanza K, Coppola A, Ni M, Song H, Wei Y, Atwal GS, Macdonald L, Oristian NS, Poueymirou W, Jankovic V, Fury M, Lowy I, Murphy AJ, Sleeman MA, Wang B, Skokos D. Cancer cell-derived type I interferons instruct tumor monocyte polarization. Cell Rep 2022; 41:111769. [PMID: 36476866 DOI: 10.1016/j.celrep.2022.111769] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 06/29/2022] [Accepted: 11/11/2022] [Indexed: 12/12/2022] Open
Abstract
Monocytes are highly plastic immune cells that modulate antitumor immunity. Therefore, identifying factors that regulate tumor monocyte functions is critical for developing effective immunotherapies. Here, we determine that endogenous cancer cell-derived type I interferons (IFNs) control monocyte functional polarization. Guided by single-cell transcriptomic profiling of human and mouse tumors, we devise a strategy to distinguish and separate immunostimulatory from immunosuppressive tumor monocytes by surface CD88 and Sca-1 expression. Leveraging this approach, we show that cGAS-STING-regulated cancer cell-derived IFNs polarize immunostimulatory monocytes associated with anti-PD-1 immunotherapy response in mice. We also demonstrate that immunosuppressive monocytes convert into immunostimulatory monocytes upon cancer cell-intrinsic cGAS-STING activation. Consistently, we find that human cancer cells can produce type I IFNs that polarize monocytes, and our immunostimulatory monocyte gene signature is enriched in patient tumors that respond to anti-PD-1 immunotherapy. Our work exposes a role for cancer cell-derived IFNs in licensing monocyte functions that influence immunotherapy outcomes.
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Affiliation(s)
- Dylan Kwart
- Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA
| | - Jing He
- Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA
| | | | | | | | | | - Patrick Poon
- Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA
| | - Xuan Ye
- Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA
| | | | | | | | | | | | - Joyce Chiu
- Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA
| | | | | | | | | | | | | | - Min Ni
- Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA
| | - Hang Song
- Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA
| | - Yi Wei
- Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA
| | | | | | | | | | | | - Matthew Fury
- Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA
| | - Israel Lowy
- Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA
| | | | | | - Bei Wang
- Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA.
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Lanza M, Casili G, Campolo M, Paterniti I, Colarossi C, Mare M, Giuffrida R, Caffo M, Esposito E, Cuzzocrea S. Immunomodulatory Effect of Microglia-Released Cytokines in Gliomas. Brain Sci 2021; 11:brainsci11040466. [PMID: 33917013 PMCID: PMC8067679 DOI: 10.3390/brainsci11040466] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/16/2021] [Accepted: 04/02/2021] [Indexed: 12/11/2022] Open
Abstract
Microglia, a type of differentiated tissue macrophage, are considered to be the most plastic cell population of the central nervous system (CNS). Microglia substantially contribute to the growth and invasion of tumor mass in brain tumors including glioblastoma (GB). In response to pathological conditions, resting microglia undergo a stereotypic activation process and become capable of phagocytosis, antigen presentation, and lymphocyte activation. Considering their immune effector function, it is not surprising to see microglia accumulation in almost every CNS disease process, including malignant brain tumors. Large numbers of glioma associated microglia and macrophages (GAMs) can accumulate within the tumor where they appear to have an important role in prognosis. GAMs constitute the largest portion of tumor infiltrating cells, contributing up to 30% of the entire glioma mass and upon interaction with neoplastic cells. GAMs acquire a unique phenotype of activation, including both M1 and M2 specific markers. It has been demonstrated that microglia possess a dual role: on one hand, microglia may represent a CNS anti-tumor response, which is inactivated by local secretion of immunosuppressive factors by glioma cells. On the other hand, taking into account that microglia are capable of secreting a variety of immunomodulatory cytokines, it is possible that they are attracted by gliomas to promote tumor growth. A better understanding of microglia-glioma interaction will be helpful in designing novel immune-based therapies against these fatal tumors. Concluding, as microglia significantly may contribute to glioma biology, favoring tumor growth and invasiveness, these cells represent a valuable alternative/additional target for the development of more effective treatments for gliomas.
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Affiliation(s)
- Marika Lanza
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 98166 Messina, Italy; (M.L.); (G.C.); (M.C.); (I.P.); (S.C.)
| | - Giovanna Casili
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 98166 Messina, Italy; (M.L.); (G.C.); (M.C.); (I.P.); (S.C.)
| | - Michela Campolo
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 98166 Messina, Italy; (M.L.); (G.C.); (M.C.); (I.P.); (S.C.)
| | - Irene Paterniti
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 98166 Messina, Italy; (M.L.); (G.C.); (M.C.); (I.P.); (S.C.)
| | - Cristina Colarossi
- Mediterranean Institute of Oncology, Via Penninazzo 7, 95029 Viagrande, Italy; (C.C.); (M.M.)
| | - Marzia Mare
- Mediterranean Institute of Oncology, Via Penninazzo 7, 95029 Viagrande, Italy; (C.C.); (M.M.)
| | | | - Maria Caffo
- Department of Biomedical and Dental Sciences and Morpho-Functional Imaging, Unit of Neurosurgery, University of Messina, 98122 Messina, Italy;
| | - Emanuela Esposito
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 98166 Messina, Italy; (M.L.); (G.C.); (M.C.); (I.P.); (S.C.)
- Correspondence:
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 98166 Messina, Italy; (M.L.); (G.C.); (M.C.); (I.P.); (S.C.)
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Abstract
There is an urgent need for improved cancer immunotherapies. The nanoparticles described here deliver genes to stimulate the immune system to specifically kill tumor cells. This synthetic, biodegradable system avoids the use of common gene delivery materials like viruses that can have safety concerns and manufacturing limitations. Local nanoparticle delivery evades adverse side effects stemming from systemic administration of immune-activating therapeutics. Importantly, this technology causes a tumor-targeting response but does not require prior knowledge of a particular patient’s gene expression profile; thus, it can serve as a platform to combat many different solid cancers. Moreover, local nanoparticle administration causes a systemic cellular immune response, which has the potential to lead to better outcomes in the context of recurrence or metastasis. Cancer immunotherapy has been the subject of extensive research, but highly effective and broadly applicable methods remain elusive. Moreover, a general approach to engender endogenous patient-specific cellular therapy, without the need for a priori knowledge of tumor antigen, ex vivo cellular manipulation, or cellular manufacture, could dramatically reduce costs and broaden accessibility. Here, we describe a biotechnology based on synthetic, biodegradable nanoparticles that can genetically reprogram cancer cells and their microenvironment in situ so that the cancer cells can act as tumor-associated antigen-presenting cells (tAPCs) by inducing coexpression of a costimulatory molecule (4-1BBL) and immunostimulatory cytokine (IL-12). In B16-F10 melanoma and MC38 colorectal carcinoma mouse models, reprogramming nanoparticles in combination with checkpoint blockade significantly reduced tumor growth over time and, in some cases, cleared the tumor, leading to long-term survivors that were then resistant to the formation of new tumors upon rechallenge at a distant site. In vitro and in vivo analyses confirmed that locally delivered tAPC-reprogramming nanoparticles led to a significant cell-mediated cytotoxic immune response with systemic effects. The systemic tumor-specific and cell-mediated immunotherapy response was achieved without requiring a priori knowledge of tumor-expressed antigens and reflects the translational potential of this nanomedicine.
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Hernandez-Alcoceba R, Sangro B, Berraondo P, Gonzalez-Aseguinolaza G, Prieto J. Cytokines for the treatment of gastrointestinal cancers: clinical experience and new perspectives. Expert Opin Investig Drugs 2013; 22:827-41. [PMID: 23594171 DOI: 10.1517/13543784.2013.793307] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Cytokines are key mediators of the immune system and have been proposed as therapeutic agents against cancer, either as recombinant proteins, or as transgenes in gene therapy approaches. Stimulation of immune responses against cancer cells is an appealing method to treat tumors with high risk of relapse and systemic dissemination. AREAS COVERED We provide a critical overview of clinical trials involving the use of cytokines for the treatment of liver, colon and pancreatic cancers. Special attention has been paid to advances in the field of gene therapy and oncolytic viruses. The potential of new developments still in a pre-clinical stage is also discussed. We have revised public sources of information (PubMed, US National Institutes of Health clinical trials database) up to January 2013. EXPERT OPINION The complexity of the immune system and the unfavorable pharmacokinetic properties of cytokines limit the efficacy of these molecules as single agents for the treatment of cancer. Expression from gene therapy vectors, together with new methods of targeting and stabilization, may overcome these hurdles. We believe cytokines will play a crucial role as part of combined approaches, enhancing the action of adoptive cell immunotherapy, oncolytic viruses or biological therapies.
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Affiliation(s)
- Ruben Hernandez-Alcoceba
- CIMA, University of Navarra, Division of Hepatology and Gene Therapy, Foundation for Applied Medical Research, Pamplona, Spain
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Omori R, Eguchi J, Hiroishi K, Ishii S, Hiraide A, Sakaki M, Doi H, Kajiwara A, Ito T, Kogo M, Imawari M. Effects of interferon-α-transduced tumor cell vaccines and blockade of programmed cell death-1 on the growth of established tumors. Cancer Gene Ther 2012; 19:637-43. [PMID: 22790963 DOI: 10.1038/cgt.2012.42] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Interferon-alpha (IFN-α) has strong antitumor effects, and IFN-α gene therapy has been used clinically against some cancers. In this study, we evaluated the efficacy of the combination of IFN-α-transduced tumor cell vaccines and programmed cell death 1 (PD-1) blockade, and investigated the mechanisms of the antitumor effects of the combined therapy. A poorly immunogenic murine colorectal cancer cell line, MC38, was transduced to overexpress IFN-α. In a therapeutic model, parental tumor-bearing mice were inoculated with MC38-IFNα cells and an anti-PD-1 antagonistic antibody. Analyses of immunohistochemistry and tumor-specific lysis were performed. The outgrowth of the established tumors was significantly reduced in mice treated with the combination of IFN-α and anti-PD-1. Immunohistochemical analyses of the therapeutic model showed marked infiltration of CD4(+) cells and CD8(+) cells in the established MC38 tumors of mice treated with both IFN-α and anti-PD-1. Significant tumor-specific cytolysis was detected when splenocytes of mice that were treated with both IFN-α and anti-PD-1 were used as effector cells. These results suggest that blockade of the PD-1 PD-ligand enhanced the Th1-type antitumor immune responses induced by IFN-α. The combination of IFN-α gene-transduced tumor cell vaccines and PD-1 blockade may be a possible candidate for a cancer vaccine for clinical trials.
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Affiliation(s)
- R Omori
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan
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6
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Abstract
Several immunostimulant approaches have been studied in the treatment of gliomas. The advent of recombinant DNA technology led to a nonspecific immunostimulation via systemic administration of cytokines. Recently, in attempts to more closely mimic their natural activity, cytokines have been delivered by implanting genetically transduced cells or by using in vivo gene transfer techniques. The latest efforts have focused on immunostimulatory agents that act directly on antigen-presenting cells and effector cells of the immune system via pattern recognition receptors. Combining these strategies with more than one mode of immunotherapy may provide better clinical results.
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Affiliation(s)
- Nicholas Butowski
- Department of Neurological Surgery, University of California San Francisco, 400 Parnassus Avenue, A808, San Francisco, CA 94143, USA.
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Hance KW, Rogers CJ, Zaharoff DA, Canter D, Schlom J, Greiner JW. The antitumor and immunoadjuvant effects of IFN-alpha in combination with recombinant poxvirus vaccines. Clin Cancer Res 2009; 15:2387-96. [PMID: 19276249 PMCID: PMC2844936 DOI: 10.1158/1078-0432.ccr-08-1752] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE IFN-alpha is a pleiotropic cytokine possessing immunomodulatory properties that may improve the efficacy of therapeutic cancer vaccines. The aim of this study was to evaluate the effectiveness and compatibility of combining recombinant IFN-alpha with poxvirus vaccines targeting the human carcinoembryonic antigen (CEA) in murine models of colorectal and pancreatic adenocarcinomas, where CEA is a self-antigen. EXPERIMENTAL DESIGN The phenotypic and functional effects of IFN-alpha were evaluated in the draining inguinal lymph nodes of tumor-free mice. We studied the effect of the site of IFN-alpha administration (local versus distal) on antigen-specific immune responses to poxvirus vaccination. Mechanistic studies were conducted to assess the efficacy of IFN-alpha and CEA-directed poxvirus vaccines in tumor-bearing CEA transgenic mice. RESULTS We identified a dose and schedule of IFN-alpha that induced a locoregional expansion of the draining inguinal lymph nodes and improved cellular cytotoxicity (natural killer and CD8(+)) and antigen presentation. Suppression of the vaccinia virus was avoided by administering IFN-alpha distal to the site of vaccination. The combination of IFN-alpha and vaccine inhibited tumor growth, improved survival, and elicited CEA-specific CTL responses in mice with CEA(+) adenocarcinomas. In mice with pancreatic tumors, IFN-alpha slowed tumor growth, induced CTL activity, and increased CD8(+) tumor-infiltrating lymphocytes. CONCLUSIONS These data suggest that IFN-alpha can be used as a biological response modifier with antigen-directed poxvirus vaccines to yield significant therapeutic antitumor immune responses. This study provides the rationale and mechanistic insights to support a clinical trial of this immunotherapeutic strategy in patients with CEA-expressing carcinomas.
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Affiliation(s)
- Kenneth W Hance
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA
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8
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Hiraide A, Hiroishi K, Eguchi J, Ishii S, Doi H, Imawari M. Dendritic cells stimulated with cytidine-phosphate-guanosine oligodeoxynucleotides and interferon-alpha-expressing tumor cells effectively reduce outgrowth of established tumors in vivo. Cancer Sci 2008; 99:1663-9. [PMID: 18754881 PMCID: PMC11158296 DOI: 10.1111/j.1349-7006.2008.00858.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Dendritic cells (DC) are potent antigen-presenting cells that elicit immune responses to foreign antigens. We have previously demonstrated the synergistic effects of cytidine-phosphate-guanosine (CpG) oligodeoxynucleotides (ODN) and interferon (IFN)-alpha on DC maturation in vitro. In the present study, the antitumor effects of DC preincubated with IFN-alpha gene-overexpressing murine colorectal cancer MC38 cells (MC38-IFN-alpha) and CpG ODN were evaluated in a poorly immunogenic murine cancer system. When we injected DC preincubated with MC38-IFNalpha and CpG ODN subcutaneously to mice bearing MC38 wild-type tumors, the outgrowth of the established parental tumors was suppressed significantly compared with that following administration of DC with MC38-IFN-alpha (P = 0.008). All mice injected with DC preincubated with MC38-IFN-alpha and CpG ODN rejected a subsequent parental tumor challenge. Immunohistochemical and flow cytometric analyses showed that CD4(+), CD8(+), and NK1.1(+) cells markedly infiltrated the established tumors of mice treated with DC preincubated with MC38-IFN-alpha and CpG ODN. From the results in immune cell-depleted mice, CD4(+) and asialo-GM-1(+) cells seemed to contribute to the antitumor effects induced by the combination DC therapy. Furthermore, non-specific cytolysis was detected when splenocytes of mice inoculated with DC preincubated with MC38-IFNalpha and CpG ODN were used as effector cells. Using an interleukin (IL)-12-neutralizing antibody it was suggested that IL-12 stimulates natural killer cells and contributes in part to the antitumor effects induced by DC incubated with CpG ODN and IFN-alpha. As DC-based immunotherapy with CpG ODN and IFN-alpha-expressing tumor cells induces a potent antitumor immune response, it should be considered for clinical application.
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Affiliation(s)
- Ayako Hiraide
- Department of Gastroenterology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan
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9
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Kushen MC, Sonabend AM, Lesniak MS. Current immunotherapeutic strategies for central nervous system tumors. Surg Oncol Clin N Am 2008; 16:987-1004, xii. [PMID: 18022555 DOI: 10.1016/j.soc.2007.07.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Immunotherapy has emerged as a promising tool in the management of malignant central nervous system tumors. Despite improvement in patient survival, traditional approaches, which consist mostly of surgery, radiotherapy, and chemotherapy, have been largely unsuccessful in permanently controlling these aggressive tumors. Immunotherapeutic strategies offer not only a novel approach but also an advantage in a way other modalities have been failing. Specifically, the capabilities of the immune system to recognize altered cells while leaving normal cells intact offer tremendous advantage over the conventional therapeutic approaches. This article summarizes our current understanding of immunotherapeutic treatment modalities used in clinical trials for management of malignant central nervous system tumors.
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Affiliation(s)
- Medina C Kushen
- Neurosurgical Oncology and The University of Chicago Brain Tumor Center, Section of Neurosurgery, The University of Chicago Hospital, 5841 South Maryland Avenue, Chicago, IL 60637, USA
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10
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Numasaki M, Tagawa M, Iwata F, Suzuki T, Nakamura A, Okada M, Iwakura Y, Aiba S, Yamaya M. IL-28 elicits antitumor responses against murine fibrosarcoma. THE JOURNAL OF IMMUNOLOGY 2007; 178:5086-98. [PMID: 17404291 DOI: 10.4049/jimmunol.178.8.5086] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
IL-28 is a recently described antiviral cytokine. In this study, we investigated the biological effects of IL-28 on tumor growth to evaluate its antitumor activity. IL-28 or retroviral transduction of the IL-28 gene into MCA205 cells did not affect in vitro growth, whereas in vivo growth of MCA205IL-28 was markedly suppressed along with survival advantages when compared with that of controls. When the metastatic ability of IL-28-secreting MCA205 cells was compared with that of controls, the expression of IL-28 resulted in a potent inhibition of metastases formation in the lungs. IL-28-mediated suppression of tumor growth was mostly abolished in irradiated mice, indicating that irradiation-sensitive cells, presumably immune cells, are primarily involved in the IL-28-induced suppression of tumor growth. In vivo cell depletion experiments displayed that polymorphonuclear neutrophils, NK cells, and CD8 T cells, but not CD4 T cells, play an equal role in the IL-28-mediated inhibition of in vivo tumor growth. Consistent with these findings, inoculation of MCA205IL-28 into mice evoked enhanced IFN-gamma production and cytotoxic T cell activity in spleen cells. Antitumor action of IL-28 is partially dependent on IFN-gamma and is independent of IL-12, IL-17, and IL-23. IL-28 increased the total number of splenic NK cells in SCID mice and enhanced IL-12-induced IFN-gamma production in vivo and expanded spleen cells in C57BL/6 mice. Moreover, IL-12 augmented IL-28-mediated antitumor activity in the presence or absence of IFN-gamma. These findings indicate that IL-28 has bioactivities that induce innate and adaptive immune responses against tumors.
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Affiliation(s)
- Muneo Numasaki
- Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Sendai, Japan.
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Ferrantini M, Capone I, Belardelli F. Interferon-alpha and cancer: mechanisms of action and new perspectives of clinical use. Biochimie 2007; 89:884-93. [PMID: 17532550 DOI: 10.1016/j.biochi.2007.04.006] [Citation(s) in RCA: 197] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2007] [Accepted: 04/12/2007] [Indexed: 01/20/2023]
Abstract
Interferons-alpha (IFN-alpha) are pleiotropic cytokines belonging to type I IFNs, extensively used in the treatment of patients with some types of cancer and viral disease. IFN-alpha can affect tumor cell functions by multiple mechanisms. In addition, these cytokines can promote the differentiation and activity of host immune cells. Early studies in mouse tumor models showed the importance of host immune mechanisms in the generation of a long-lasting antitumor response after treatment of the animals with IFN-alpha/beta. Subsequently, an ensemble of studies based on the use of genetically modified tumor cells expressing specific IFN molecules provided important information on the host-mediated antitumor mechanisms induced by the local production of IFN-alpha. Of note, several studies have then underscored new immunomodulatory effects of IFN-alpha, including activities on T cells and dendritic cells, which may lead to IFN-induced antitumor immunity. In addition, recent reports on new immune correlates in cancer patients responding to IFN-alpha represent additional evidence on the importance of the interactions of IFN-alpha with the immune system for the generation of a durable antitumor response. On the whole, this knowledge suggests the advantage of using these cytokines as adjuvants of cancer vaccines and for the in vitro generation of highly active dendritic cells to be utilized for therapeutic vaccination of cancer patients.
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Affiliation(s)
- Maria Ferrantini
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
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12
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Ishii S, Hiroishi K, Eguchi J, Hiraide A, Imawari M. Dendritic cell therapy with interferon-alpha synergistically suppresses outgrowth of established tumors in a murine colorectal cancer model. Gene Ther 2006; 13:78-87. [PMID: 16107857 DOI: 10.1038/sj.gt.3302608] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Both dendritic cell (DC)-based immunotherapy and interferon (IFN)-alpha therapy have been proved to have potent long-lasting antitumor effects. In anticipation of synergistic antitumor effects, we performed combination therapy with DCs and IFN-alpha gene-transduced murine colorectal cancer MC38 cells (MC38-IFN-alpha). DCs incubated with MC38-IFN-alpha, but not neomycin-resistance gene-transduced MC38 cells (MC38-Neo), effectively enhanced proliferation of allogeneic splenocytes in vitro. In 12 of 17 mice, DCs in combination with MC38-IFN-alpha prevented the development of a parental tumor, while DCs and MC38-Neo did in only three of 17 mice (P=0.008). In a therapeutic model of an established parental tumor, inoculation of DCs and MC38-IFN-alpha suppressed the growth of the established parental tumors significantly compared with the administration of DCs with MC38-Neo or naive splenocytes with MC38-IFN-alpha (P=0.016 and 0.024, respectively). Analyses of immunohistochemistry and tumor-infiltrating mononuclear cells showed that CD8(+), CD11c(+), and NK1.1(+) cells markedly infiltrated the established tumors of mice treated with DCs and MC38-IFN-alpha. From the results of observation of parental tumor outgrowth in immune cell-depleted mice, CD8(+) cells, and asialo-GM-1(+) cells were thought to contribute to the antitumor effects induced by the combination therapy. Furthermore, MC38-specific cytolysis was detected when splenocytes of mice inoculated with DCs and MC38-IFN-alpha cells were stimulated with MC38-IFN-alpha cells in vitro. Since DC-based immunotherapy in combination with IFN-alpha-expressing tumor cells induces potent antitumor cellular immune responses, it should be considered for clinical application.
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Affiliation(s)
- S Ishii
- Second Department of Internal Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan
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13
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Sikorski CW, Lesniak MS. Immunotherapy for malignant glioma: current approaches and future directions. Neurol Res 2005; 27:703-16. [PMID: 16197807 DOI: 10.1179/016164105x49481] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Traditional therapies for the treatment of malignant glioma have failed to make appreciable gains regarding patient outcome in the last decade. Therefore, immunotherapeutic approaches have become increasingly popular in the treatment of this cancer. This article reviews general immunology of the central nervous system and the immunobiology of malignant glioma to provide a foundation for understanding the rationale behind current glioma immunotherapies. A review of currently implemented immunological treatments is then provided with special attention paid to the use of vaccines, gene therapy, cytokines, dendritic cells and viruses. Insights into future and developing avenues of glioma immunotherapy, such as novel delivery systems, are also discussed.
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Affiliation(s)
- Christian W Sikorski
- Division of Neurosurgery, The University of Chicago Pritzker School of Medicine, 5841 South Maryland Avenue, MC 3026, Chicago, Illinois 60637, USA
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14
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Lichtor T, Glick RP, Lin H, O-Sullivan I, Cohen EP. Intratumoral injection of IL-secreting syngeneic/allogeneic fibroblasts transfected with DNA from breast cancer cells prolongs the survival of mice with intracerebral breast cancer. Cancer Gene Ther 2005; 12:708-14. [PMID: 15803143 DOI: 10.1038/sj.cgt.7700832] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Prior studies have revealed the immunotherapeutic properties of a vaccine prepared by transfer of genomic DNA from breast cancer cells into a highly immunogenic cell line. The rationale for this type of vaccine is that genes specifying an array of weakly immunogenic, unique tumor antigens associated with the malignant cells will be expressed in a highly immunogenic form by the transfected cells. Here, the immunotherapeutic properties of a vaccine prepared by transfection of mouse fibroblasts with DNA from a breast carcinoma (SB-5b) that arose spontaneously in a C3H/He mouse (H-2Kb) were tested in mice with intracerebral breast cancer. To augment their nonspecific immunogenic properties, before DNA transfer, the fibroblasts (of C3H/He mouse origin) were modified to express allogeneic MHC class I H-2Kb-determinants and to secrete IL-2, IL-18 or GM-CSF. The results indicate that C3H/He mice injected intracerebrally (i.c.) with the breast cancer cells and syngeneic/allogeneic-transfected fibroblasts modified to secrete IL-2 survived significantly longer (P < .005) than mice in various control groups, including mice injected i.c. with the breast cancer cells alone. The immunotherapeutic properties of transfected fibroblasts modified to secrete IL-18 or GM-CSF were less efficacious. The results of two independent in vitro cytotoxicity assays indicate that systemic cellular antitumor immunity was generated in mice injected i.c. with the transfected cells, and the immunity was mediated predominantly by CD8+ T cells.
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Affiliation(s)
- Terry Lichtor
- Department of Neurosurgery, Rush University Medical Center, John H Stroger Hospital of Cook County, Chicago, Illinois 60612, USA.
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15
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Eguchi J, Hiroishi K, Ishii S, Baba T, Matsumura T, Hiraide A, Okada H, Imawari M. Interleukin-4 gene transduced tumor cells promote a potent tumor-specific Th1-type response in cooperation with interferon-alpha transduction. Gene Ther 2005; 12:733-41. [PMID: 15772692 DOI: 10.1038/sj.gt.3302401] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
To investigate antitumor mechanisms in interleukin (IL)-4 therapy, we established an IL-4-overexpressing MC38 murine colorectal cancer cell line (MC38-IL4). As a therapy against established tumors, MC38-IL4 cells were inoculated contralaterally 7 days after wild-type (MC38-WT) cells had been injected, significantly reducing growth of wild-type tumors (P=0.030). Immunohistochemical analysis showed numerous granulocytes infiltrating wild-type tumors of MC38-IL4-inoculated mice. Injection of MC38-IL4 cells in leukocyte-depleted mice confirmed that granulocytes were involved in IL-4-related primary antitumor effects. Inoculation of MC38-WT in leukocyte-depleted mice initially injected with MC38-IL4 suggested that T cells contributed to the antitumor effects. To investigate tumor-specific responses, we stimulated splenocytes of MC38-immune mice with MC38-IL4 cells in vitro, resulting in MC38-specific lysis (57.5+/-7.2%, effector to target ratio=20). Treatment of established wild-type tumors with MC38-IL4 in combination with interferon (IFN)-alpha-overexpressing MC38 cells (MC38-IFNalpha) significantly reduced the growth of wild-type tumors (P=0.009). In vitro IFN-gamma production by splenocytes from mice injected with both MC38-IL4 and -IFNalpha was greatly enhanced in comparison with MC38-IL4 alone, while IL-10 production was not increased. Thus, granulocytes concern early antitumor effects of IL-4 therapy. Subsequently, IL-4 induces long-lasting, tumor-specific immune responses. IL-4 appears to promote a T-helper 1-type antitumor immune response, which is enhanced in cooperation with IFN-alpha.
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Affiliation(s)
- J Eguchi
- Second Department of Internal Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan
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16
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Abstract
Despite advances in surgical and adjuvant therapy, the prognosis for malignant gliomas remains dismal. Malignant gliomas, like other malignancies, are able to overcome host immune defences through a variety of mechanisms that have become increasingly well-characterised over the past decade. However, this 'immunologically privileged' status of the brain is not absolute. Systemic immunisation with brain-specific antigens can induce immune responses that are manifested in the CNS, such as experimental allergic encephalomyelitis. The efficacy of peripheral immunisation against brain tumours has also been demonstrated in preclinical models. Based on these observations, clinical trials of peripheral immunisations with brain tumour-derived antigens have been initiated. A limitation of this approach is that the immunological environment within brain tumours is suboptimal for functions of antitumour immune effector cells. As a means to overcome this issue, delivery of cytokine genes to the tumour site may reverse the inhibitory immunological environment of the brain tumours and enhance the efficacy of peripheral vaccine-induced immune effector cells. The brain tumour environment may also be rendered more immunologically favourable by the delivery of additional antigen-presenting cells that can provide infiltrating effector cells with secondary activation signals. Indeed, the authors' recent data indicate that the injection of intracranial tumours with dendritic cells secreting interferon-alpha enhances the efficacy of peripheral vaccinations with tumour-specific antigens by cross-priming tumour antigen-specific T cells in the cervical lymph nodes. This review highlights the recent literature on cytokine gene therapy for brain tumours, and proposes the effective use of cytokine gene delivery both at the site of vaccines (i.e., the site of antigen presentation) and within the target brain tumours (i.e., the site where the effector cells exert their antitumour immunity). Successful immunogene therapy for brain tumours requires detailed understanding of cytokine functions and the use of them at the appropriate stages/sites of the immunological milieu.
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Affiliation(s)
- Hideho Okada
- University of Pittsburgh Medical Center/Cancer Institute, Department of Neurological Surgery, Brain Tumor Program, G12.a Research Pavilion at the Hillman Cancer Center, 5117 Centre Ave, Pittsburgh, PA 15213-1863, USA.
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17
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de Gruijl TD, Pinedo HM, Scheper RJ. Immunotherapy of Cancer by Dendritic Cell-Targeted Gene Transfer. Cancer Gene Ther 2005. [DOI: 10.1007/978-1-59259-785-7_10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Eguchi JI, Hiroishi K, Ishii S, Mitamura K. Interferon-alpha and interleukin-12 gene therapy of cancer: interferon-alpha induces tumor-specific immune responses while interleukin-12 stimulates non-specific killing. Cancer Immunol Immunother 2003; 52:378-86. [PMID: 12739068 PMCID: PMC11033005 DOI: 10.1007/s00262-002-0367-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2002] [Accepted: 11/13/2002] [Indexed: 01/08/2023]
Abstract
Cytokine gene therapy is applied in clinical studies of tumors, and IFN-alpha and IL-12 are widely used for cancer immunotherapy. Using a poorly immunogenic murine colorectal cancer cell line, MC38, we compared antitumor effects of IFN-alpha and IL-12. Transduced MC38 cell lines expressing IFN-alpha or IL-12 (MC38-IFNalpha or MC38-IL12, respectively) were established using retroviral vectors. Transduction of IFN-alpha or IL-12 gene to MC38 cells significantly reduced tumorigenicity in immunocompetent mice. When tumor-free mice initially injected with MC38-IFNalpha or MC38-IL12 cells were reinjected contralaterally with wild-type MC38 cells (MC38-WT) after 35 days, 7 of 12 or 2 of 12 mice rejected MC38-WT cells, respectively. In therapy-model mice with established tumor derived from MC38-WT cells, inoculation of gene-transduced cells significantly suppressed growth of the tumor in MC38-IFNalpha-inoculated groups, but not in the IL-12-inoculated group. Immunohistologic and flow cytometric analyses showed marked infiltration of CD8(+) cells in wild-type tumors of mice inoculated with IFN-alpha-expressing cells. Leukocyte-depletion experiments implicated CD8(+) T cells in tumor rejection induced by IFN-alpha-transduction; both CD8(+) T cells and natural killer cells were implicated in the more modest antitumor effect from IL-12 expression. To investigate induction of tumor-specific immune responses, we stimulated splenocytes from tumor-free mice twice in vitro with genetically modified MC38 cells. In vitro stimulations with MC38-IFNalpha cells induced definite MC38-specific lysis, but not stimulations with MC38-IL-12 cells. Injecting combination of MC38-IFNalpha and MC38-IL-12 cells caused an additive antitumor effect in the therapy model. These data suggested that IFN-alpha induces cytotoxic T lymphocytes and elicits long-lasting tumor-specific immunity, whereas IL-12 seems to stimulate non-specific killing. With additional refinements, combined IFN-alpha and IL-12 gene therapy might warrant clinical trials.
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Affiliation(s)
- Jun-ichi Eguchi
- Second Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku,, 142-8666 Tokyo, Japan
| | - Kazumasa Hiroishi
- Second Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku,, 142-8666 Tokyo, Japan
| | - Shigeaki Ishii
- Second Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku,, 142-8666 Tokyo, Japan
| | - Keiji Mitamura
- Second Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku,, 142-8666 Tokyo, Japan
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Belardelli F, Ferrantini M, Proietti E, Kirkwood JM. Interferon-alpha in tumor immunity and immunotherapy. Cytokine Growth Factor Rev 2002; 13:119-34. [PMID: 11900988 DOI: 10.1016/s1359-6101(01)00022-3] [Citation(s) in RCA: 246] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Interferon-alpha (IFN-alpha) is a pleiotropic cytokine belonging to type I IFN, currently used in cancer patients. Early studies in mouse tumor models have shown the importance of host immune mechanisms in the generation of a long-lasting antitumor response to type I IFN. Recent studies have underscored new immunomodulatory effects of IFN-alpha, including activities on T and dendritic cells, which may explain IFN-induced tumor immunity. Reports on new immune correlates in cancer patients responding to IFN-alpha represent additional evidence on the importance of the interactions of IFN-alpha with the immune system for the generation of durable antitumor response. This knowledge, together with results from studies on genetically modified tumor cells expressing IFN-alpha, suggest novel strategies for using these cytokines in cancer immunotherapy and in particular the use of IFN-alpha as an immune adjuvant for the development of cancer vaccines.
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Affiliation(s)
- Filippo Belardelli
- Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
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Xu CT, Huang LT, Pan BR. Current gene therapy for stomach carcinoma. World J Gastroenterol 2001; 7:752-9. [PMID: 11819868 PMCID: PMC4695588 DOI: 10.3748/wjg.v7.i6.752] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2001] [Revised: 05/29/2001] [Accepted: 06/06/2001] [Indexed: 02/06/2023] Open
Affiliation(s)
- C T Xu
- Editorial Department, the Journal of Fourth Military Medical University, Xi'an, Shaanxi Province, China.
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Tamura T, Nishi T, Goto T, Takeshima H, Dev SB, Ushio Y, Sakata T. Intratumoral delivery of interleukin 12 expression plasmids with in vivo electroporation is effective for colon and renal cancer. Hum Gene Ther 2001; 12:1265-76. [PMID: 11440620 DOI: 10.1089/104303401750270922] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
We report on an antitumor treatment involving electrogene therapy (EGT), a newly developed in vivo gene transfer method using electroporation. We carried out in vivo EGT in a subcutaneous model of CT26 colon carcinoma cells, using plasmid DNAs encoding interleukin 12 (IL-12) subunits. For this purpose, we developed two IL-12 expression systems: a cotransfer system using a plasmid encoding the IL-12 p40 subunit and a plasmid encoding the IL-12 p35 subunit, and a single-vector system using a plasmid expressing a p40-p35 fusion protein. Both transfer systems significantly inhibited the growth of CT26 tumor. Immunohistochemical analysis of IL-12 EGT-treated tumors revealed enhanced infiltration of CD8(+) cells into the tumor tissue, while reverse transcriptase-polymerase chain reaction confirmed the increased expression of interferon gamma within treated tumors. The same IL-12 EGT applied to the nude mouse model was not effective, suggesting the critical role of T cell infiltration in this treatment. The inhibitory effects revealed in experiments in which previously treated mice were rechallenged with a second inoculation of CT26 tumor cells suggested that IL-12 EGT may also establish partial systemic antitumor immunity. The growth of IL-12 EGT-treated Renca tumors, a renal cell carcinoma, was also significantly inhibited. These findings suggest that EGT of the IL-12 gene has the potential to be an effective anticancer gene therapy.
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Affiliation(s)
- T Tamura
- Shionogi Institute for Medical Science, 2-5-1, Mishima, Settsu-shi, Osaka 566-0022, Japan
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Ferrantini M, Belardelli F. Gene therapy of cancer with interferon: lessons from tumor models and perspectives for clinical applications. Semin Cancer Biol 2000; 10:145-57. [PMID: 10936064 DOI: 10.1006/scbi.2000.0333] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Cytokine gene transfer is a current approach in studies of gene therapy of cancer IFNs represent valuable cytokines for these studies, since they exert multiple biological effects, including anti-tumor activities. Early studies have been focused on IFN-gamma. Recently, several reports have shown that the transfer of type I IFN (especially IFN-alpha) genes represents a powerful approach for inducing tumor suppression. Recent studies have underscored new IFN-induced activities on immune cells. This knowledge adds a further rationale for the use of IFN-alpha in strategies of gene therapy of cancer and can be exploited for the design of more selective and effective anticancer treatments.
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Affiliation(s)
- M Ferrantini
- Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy
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Hiroishi K, Tüting T, Lotze MT. IFN-alpha-expressing tumor cells enhance generation and promote survival of tumor-specific CTLs. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2000; 164:567-72. [PMID: 10623796 DOI: 10.4049/jimmunol.164.2.567] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
IFN-alpha gene therapy has been successfully applied in several tumor models. Our studies involving the murine colorectal adenocarcinoma cell line MC38 confirm that IFN-alpha transduction of a poorly immunogenic tumor cell reduces tumorigenicity and leads to long-lasting tumor immunity. To investigate the effect of IFN-alpha transduction on the development of antitumor immune responses, we restimulated splenocytes from MC38-immune mice in vitro. Detection of MC38-specific cytotoxicity was markedly enhanced when murine IFN-alpha2-transduced MC38 (MC38-IFNalpha) or CD80-transduced MC38 (MC38-CD80) was used for restimulation compared with wild type (MC38-WT) or neomycin resistance gene-transduced MC38 (MC38-Neo) cells. MC38-specific CD8+ CTL line and clone were established from splenocytes of mouse immunized with MC38-IFNalpha. Stimulation with MC38-IFNalpha as well as MC38-CD80 enhanced the proliferation of MC38-specific CTLs in vitro much more effectively than stimulation with WT or MC38-Neo (p < 0.05). Coincubation of MC38-specific CTLs with MC38-IFNalpha or MC38-CD80 resulted in significantly less DNA fragmentation (8.0% and 12.8%, respectively) compared with coincubation of the CTLs with MC38-WT (43.5%; p < 0.001) or MC38-Neo cells (38.1%; p < 0.003). These results suggest that prevention of apoptotic cell death in tumor-specific CTLs may be one mechanism by which IFN-alpha-expressing tumor cells can promote the generation of antitumor immunity. The effect of IFN-alpha on CTLs appears to be similar to that of CD80, which also prevents apoptotic cell death after stimulation of T lymphocytes.
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MESH Headings
- Adjuvants, Immunologic/biosynthesis
- Adjuvants, Immunologic/genetics
- Adjuvants, Immunologic/physiology
- Adoptive Transfer
- Animals
- B7-1 Antigen/genetics
- B7-1 Antigen/physiology
- Cell Survival/genetics
- Cell Survival/immunology
- Colorectal Neoplasms/immunology
- DNA Fragmentation/immunology
- DNA, Neoplasm/metabolism
- Epitopes, T-Lymphocyte/immunology
- Female
- Interferon-alpha/biosynthesis
- Interferon-alpha/genetics
- Interferon-alpha/physiology
- Lymphocyte Activation/genetics
- Lymphocyte Activation/immunology
- Mice
- Mice, Inbred C57BL
- Neoplasm Transplantation
- T-Lymphocytes, Cytotoxic/cytology
- T-Lymphocytes, Cytotoxic/immunology
- T-Lymphocytes, Cytotoxic/metabolism
- Tumor Cells, Cultured/immunology
- Tumor Cells, Cultured/metabolism
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Affiliation(s)
- K Hiroishi
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
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