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Ye Y, Xu C, Chen F, Liu Q, Cheng N. Targeting Innate Immunity in Breast Cancer Therapy: A Narrative Review. Front Immunol 2021; 12:771201. [PMID: 34899721 PMCID: PMC8656691 DOI: 10.3389/fimmu.2021.771201] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 11/08/2021] [Indexed: 01/07/2023] Open
Abstract
Although breast cancer has been previously considered "cold" tumors, numerous studies are currently conducted to explore the great potentials of immunotherapies in improving breast cancer patient outcomes. In addition to the focus on stimulating adaptive immunity for antitumor responses, growing evidence showed the importance of triggering host innate immunity to eradicate established tumors and/or control tumor metastasis of breast cancer. In this review, we first briefly introduce the breast tumor immune microenvironment. We also discuss innate immune targets and pathways and mechanisms of their synergy with the adaptive antitumor response and other treatment strategies. Lastly, we review clinical trials targeting innate immune pathways for breast cancer therapies.
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Affiliation(s)
- Yanqi Ye
- Zenomics. Inc. Magnify at California NanoSystems Institute, Los Angeles, CA, United States
| | - Chun Xu
- School of Dentistry, The University of Queensland, Brisbane, QLD, Australia
| | - Fengqian Chen
- School of Medicine, University of Maryland, Baltimore, MD, United States
| | - Qi Liu
- School of Medicine, Johns Hopkins University, Baltimore, MD, United States
| | - Ning Cheng
- Department of Otolaryngology - Head and Neck Surgery, University of California at San Francisco, San Francisco, CA, United States
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Williams MM, Hafeez SA, Christenson JL, O’Neill KI, Hammond NG, Richer JK. Reversing an Oncogenic Epithelial-to-Mesenchymal Transition Program in Breast Cancer Reveals Actionable Immune Suppressive Pathways. Pharmaceuticals (Basel) 2021; 14:ph14111122. [PMID: 34832904 PMCID: PMC8622696 DOI: 10.3390/ph14111122] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 12/16/2022] Open
Abstract
Approval of checkpoint inhibitors for treatment of metastatic triple negative breast cancer (mTNBC) has opened the door for the use of immunotherapies against this disease. However, not all patients with mTNBC respond to current immunotherapy approaches such as checkpoint inhibitors. Recent evidence demonstrates that TNBC metastases are more immune suppressed than primary tumors, suggesting that combination or additional immunotherapy strategies may be required to activate an anti-tumor immune attack at metastatic sites. To identify other immune suppressive mechanisms utilized by mTNBC, our group and others manipulated oncogenic epithelial-to-mesenchymal transition (EMT) programs in TNBC models to reveal differences between this breast cancer subtype and its more epithelial counterpart. This review will discuss how EMT modulation revealed several mechanisms, including tumor cell metabolism, cytokine milieu and secretion of additional immune modulators, by which mTNBC cells may suppress both the innate and adaptive anti-tumor immune responses. Many of these pathways/proteins are under preclinical or clinical investigation as therapeutic targets in mTNBC and other advanced cancers to enhance their response to chemotherapy and/or checkpoint inhibitors.
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Viroimmunotherapy for breast cancer: promises, problems and future directions. Cancer Gene Ther 2020; 28:757-768. [PMID: 33268826 DOI: 10.1038/s41417-020-00265-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 08/26/2020] [Accepted: 11/12/2020] [Indexed: 02/07/2023]
Abstract
Virotherapy, a strategy to use live viruses as therapeutics, is a relatively novel field in the treatment of cancer. With the advancements in molecular biology and virology, there has been a huge increase in research on cancer virotherapy. For the treatment of cancer, viruses could be used either as vectors in gene therapy or as oncolytic agents. A variety of viruses have been studied for their potential usage in gene therapy or oncolytic therapy. In this review, we discuss virotherapy with a special focus on breast cancer. Breast cancer is the most common cancer and the leading cause of cancer-related deaths in women worldwide. Current treatments are insufficient to cure metastatic breast cancer and are often associated with severe side effects that further deteriorates patients' quality of life. Therefore, novel therapeutic approaches such as virotherapy need to be developed for the treatment of breast cancer. Here we summarize the current treatments for breast cancer and the potential use of virotherapy in the treatment of the disease. Furthermore, we discuss the use of oncolytic viruses as immunotherapeutics and the rational combination of oncolytic viruses with other therapeutics for optimal treatment of breast cancer. Finally, we outline the progress made in virotherapy for breast cancer and the shortcomings that need to be addressed for this novel therapy to move to the clinic for better treatment of breast cancer.
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Lacher MD, Bauer G, Fury B, Graeve S, Fledderman EL, Petrie TD, Coleal-Bergum DP, Hackett T, Perotti NH, Kong YY, Kwok WW, Wagner JP, Wiseman CL, Williams WV. SV-BR-1-GM, a Clinically Effective GM-CSF-Secreting Breast Cancer Cell Line, Expresses an Immune Signature and Directly Activates CD4 + T Lymphocytes. Front Immunol 2018; 9:776. [PMID: 29867922 PMCID: PMC5962696 DOI: 10.3389/fimmu.2018.00776] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 03/28/2018] [Indexed: 12/18/2022] Open
Abstract
Targeted cancer immunotherapy with irradiated, granulocyte–macrophage colony-stimulating factor (GM-CSF)-secreting, allogeneic cancer cell lines has been an effective approach to reduce tumor burden in several patients. It is generally assumed that to be effective, these cell lines need to express immunogenic antigens coexpressed in patient tumor cells, and antigen-presenting cells need to take up such antigens then present them to patient T cells. We have previously reported that, in a phase I pilot study (ClinicalTrials.gov NCT00095862), a subject with stage IV breast cancer experienced substantial regression of breast, lung, and brain lesions following inoculation with clinical formulations of SV-BR-1-GM, a GM-CSF-secreting breast tumor cell line. To identify diagnostic features permitting the prospective identification of patients likely to benefit from SV-BR-1-GM, we conducted a molecular analysis of the SV-BR-1-GM cell line and of patient-derived blood, as well as a tumor specimen. Compared to normal human breast cells, SV-BR-1-GM cells overexpress genes encoding tumor-associated antigens (TAAs) such as PRAME, a cancer/testis antigen. Curiously, despite its presumptive breast epithelial origin, the cell line expresses major histocompatibility complex (MHC) class II genes (HLA-DRA, HLA-DRB3, HLA-DMA, HLA-DMB), in addition to several other factors known to play immunostimulatory roles. These factors include MHC class I components (B2M, HLA-A, HLA-B), ADA (encoding adenosine deaminase), ADGRE5 (CD97), CD58 (LFA3), CD74 (encoding invariant chain and CLIP), CD83, CXCL8 (IL8), CXCL16, HLA-F, IL6, IL18, and KITLG. Moreover, both SV-BR-1-GM cells and the responding study subject carried an HLA-DRB3*02:02 allele, raising the question of whether SV-BR-1-GM cells can directly present endogenous antigens to T cells, thereby inducing a tumor-directed immune response. In support of this, SV-BR-1-GM cells (which also carry the HLA-DRB3*01:01 allele) treated with yellow fever virus (YFV) envelope (Env) 43–59 peptides reactivated YFV-DRB3*01:01-specific CD4+ T cells. Thus, the partial HLA allele match between SV-BR-1-GM and the clinical responder might have enabled patient T lymphocytes to directly recognize SV-BR-1-GM TAAs as presented on SV-BR-1-GM MHCs. Taken together, our findings are consistent with a potentially unique mechanism of action by which SV-BR-1-GM cells can act as APCs for previously primed CD4+ T cells.
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Affiliation(s)
| | - Gerhard Bauer
- GMP Facility, Institute for Regenerative Cures, University of California, Davis (UCD), Sacramento, CA, United States
| | - Brian Fury
- GMP Facility, Institute for Regenerative Cures, University of California, Davis (UCD), Sacramento, CA, United States
| | - Sanne Graeve
- BriaCell Therapeutics Corp., Berkeley, CA, United States
| | - Emily L Fledderman
- GMP Facility, Institute for Regenerative Cures, University of California, Davis (UCD), Sacramento, CA, United States
| | - Tye D Petrie
- GMP Facility, Institute for Regenerative Cures, University of California, Davis (UCD), Sacramento, CA, United States
| | - Dane P Coleal-Bergum
- GMP Facility, Institute for Regenerative Cures, University of California, Davis (UCD), Sacramento, CA, United States
| | - Tia Hackett
- GMP Facility, Institute for Regenerative Cures, University of California, Davis (UCD), Sacramento, CA, United States
| | - Nicholas H Perotti
- GMP Facility, Institute for Regenerative Cures, University of California, Davis (UCD), Sacramento, CA, United States
| | - Ying Y Kong
- Benaroya Research Institute at Virginia Mason, Seattle, WA, United States
| | - William W Kwok
- Benaroya Research Institute at Virginia Mason, Seattle, WA, United States
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Anders M, Hansen R, Ding RX, Rauen KA, Bissell MJ, Korn WM. Disruption of 3D tissue integrity facilitates adenovirus infection by deregulating the coxsackievirus and adenovirus receptor. Proc Natl Acad Sci U S A 2003; 100:1943-8. [PMID: 12576544 PMCID: PMC149938 DOI: 10.1073/pnas.0337599100] [Citation(s) in RCA: 82] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The human coxsackievirus and adenovirus receptor (CAR) represents the primary cellular site of adenovirus attachment during infection. An understanding of the mechanisms regulating its expression could contribute to improving efficacy and safety of adenovirus-based therapies. We characterized regulation of CAR expression in a 3D cell culture model of human breast cancer progression, which mimics aspects of the physiological tissue context in vitro. Phenotypically normal breast epithelial cells (S1) and their malignant derivative (T4-2 cells) were grown either on tissue culture plastic (2D) or 3D cultures in basement membrane matrix. S1 cells grown in 3D showed low levels of CAR, which was expressed mainly at cell-cell junctions. In contrast, T4-2 cells expressed high levels of CAR, which was mainly in the cytoplasm. When signaling through the epidermal growth factor receptor was inhibited in T4-2 cells, cells reverted to a normal phenotype, CAR protein expression was significantly reduced, and the protein relocalized to cell-cell junctions. Growth of S1 cells as 2D cultures or in 3D in collagen-I, a nonphysiological microenvironment for these cells, led to up-regulation of CAR to levels similar to those in T4-2 cells, independently of cellular growth rates. Thus, expression of CAR depends on the integrity and polarity of the 3D organization of epithelial cells. Disruption of this organization by changes in the microenvironment, including malignant transformation, leads to up-regulation of CAR, thus enhancing the cell's susceptibility to adenovirus infection.
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Affiliation(s)
- M Anders
- Cancer Research Institute, Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA
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Shi M, Wang FS, Wu ZZ. Synergetic anticancer effect of combined quercetin and recombinant adenoviral vector expressing human wild-type p53, GM-CSF and B7-1 genes on hepatocellular carcinoma cells in vitro. World J Gastroenterol 2003; 9:73-8. [PMID: 12508355 PMCID: PMC4728253 DOI: 10.3748/wjg.v9.i1.73] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: This study investigated the anti-cancer effect of combined quercetin and a recombinant adenovirus vector expressing the human p53, GM-CSF and B7-1 genes (designated BB-102) on human hepatocellular carcinoma (HCC) cell lines in vitro.
METHODS: The sensitivity of HCC cells to anticancer agents was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The viability of cells infected with BB-102 was determined by trypan blue exclusion. The expression levels of human wild-type p53, GM-CSF and B7-1 genes were determined by Western blot, enzyme-linked immunosorbent assay (ELISA) and flow cytometric analysis, respectively. The apoptosis of BB-102-infected or quercetin-treated HCC cells was detected by terminal deoxynucleotidyl transferase (TdT) assay or DNA ladder electrophoresis.
RESULTS: Quercetin was found to suppress proliferation of human HCC cell lines BEL-7402, HuH-7 and HLE, with peak suppression at 50 μmol/L quercetin. BB-102 infection was also found to significantly suppress proliferation of HCC cell lines. The apoptosis of BB-102-infected HCC cells was greater in HLE and HuH-7 cells than in BEL-7402 cells. Quercetin did not affect the expression of the three exogenous genes in BB-102-infected HCC cells (P > 0.05), but it was found to further decrease proliferation and promote apoptosis of BB-102-infected HCC cells.
CONCLUSION: BB-102 and quercetin synergetically suppress HCC cell proliferation and induce HCC cell apoptosis, suggesting a possible use as a combined anti-cancer agent.
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Affiliation(s)
- Ming Shi
- Division of Biological Engineering, Institute of Infectious Disease, the 302 Hospital of PLA, 26 Fengtai Lu, Beijing 100039, China
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