scholarly journals Chimeric antigen receptors that trigger phagocytosis

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Meghan A Morrissey ◽  
Adam P Williamson ◽  
Adriana M Steinbach ◽  
Edward W Roberts ◽  
Nadja Kern ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Immune Cell ◽  
Human Cancer ◽  
Antibody Fragment ◽  
Cell Number ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
Cell Therapies ◽  
Human Cancer Cells

Chimeric antigen receptors (CARs) are synthetic receptors that reprogram T cells to kill cancer. The success of CAR-T cell therapies highlights the promise of programmed immunity and suggests that applying CAR strategies to other immune cell lineages may be beneficial. Here, we engineered a family of Chimeric Antigen Receptors for Phagocytosis (CAR-Ps) that direct macrophages to engulf specific targets, including cancer cells. CAR-Ps consist of an extracellular antibody fragment, which can be modified to direct CAR-P activity towards specific antigens. By screening a panel of engulfment receptor intracellular domains, we found that the cytosolic domains from Megf10 and FcRɣ robustly triggered engulfment independently of their native extracellular domain. We show that CAR-Ps drive specific engulfment of antigen-coated synthetic particles and whole human cancer cells. Addition of a tandem PI3K recruitment domain increased cancer cell engulfment. Finally, we show that CAR-P expressing murine macrophages reduce cancer cell number in co-culture by over 40%.

scholarly journals Chimeric antigen receptors that trigger phagocytosis

2018 ◽  
Author(s):  
Meghan A. Morrissey ◽  
Adam P. Williamson ◽  
Adriana M. Steinbach ◽  
Edward W. Roberts ◽  
Nadja Kern ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Immune Cell ◽  
Antibody Fragment ◽  
Cell Number ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
Cell Therapies ◽  
Car T ◽  
Cytosolic Domains

AbstractChimeric antigen receptors (CARs) are synthetic receptors that reprogram T cells to kill cancer. The success of CAR-T cell therapies highlights the promise of programmed immunity, and suggests that applying CAR strategies to other immune cell lineages may be beneficial. Here, we engineered a family of Chimeric Antigen Receptors for Phagocytosis (CAR-Ps) that direct macrophages to engulf specific targets, including cancer cells. CAR-Ps consist of an extracellular antibody fragment, which can be modified to direct CAR-P activity towards specific antigens. By screening a panel of engulfment receptor intracellular domains, we found that the cytosolic domains from Megf10 and FcRγ robustly triggered engulfment independently of their native extracellular domain. We show that CAR-Ps drive specific engulfment of antigen-coated synthetic particles and whole cancer cells. Addition of a tandem PI3K recruitment domain increased cancer cell engulfment. Finally, we show that CAR-P expressing macrophages reduce cancer cell number in co-culture by over 40%.SummaryWe report the first Chimeric Antigen Receptors for Phagocytosis (CAR-Ps) that promote engulfment of antigen-coated particles and cancer cells.

scholarly journals Secretoglobin 3A2 eliminates human cancer cells through pyroptosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Shigetoshi Yokoyama ◽  
Shun Nakayama ◽  
Lei Xu ◽  
Aprile L. Pilon ◽  
Shioko Kimura
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Lung Cancer Cell ◽  
Small Cell Lung ◽  
Human Cancer Cells

AbstractNon-canonical inflammasome activation that recognizes intracellular lipopolysaccharide (LPS) causes pyroptosis, the inflammatory death of innate immune cells. The role of pyroptosis in innate immune cells is to rapidly eliminate pathogen-infected cells and limit the replication niche in the host body. Whether this rapid cell elimination process of pyroptosis plays a role in elimination of cancer cells is largely unknown. Our earlier study demonstrated that a multi-functional secreted protein, secretoglobin (SCGB) 3A2, chaperones LPS to cytosol, and activates caspase-11 and the non-canonical inflammasome pathway, leading to pyroptosis. Here we show that SCGB3A2 exhibits marked anti-cancer activity against 5 out of 11 of human non-small cell lung cancer cell lines in mouse xenographs, while no effect was observed in 6 of 6 small cell lung cancer cell lines examined. All SCGB3A2-LPS-sensitive cells express syndecan 1 (SDC1), a SCGB3A2 cell surface receptor, and caspase-4 (CASP4), a critical component of the non-canonical inflammasome pathway. Two epithelial-derived colon cancer cell lines expressing SDC1 and CASP4 were also susceptible to SCGB3A2-LPS treatment. TCGA analysis revealed that lung adenocarcinoma patients with higher SCGB3A2 mRNA levels exhibited better survival. These data suggest that SCGB3A2 uses the machinery of pyroptosis for the elimination of human cancer cells via the non-canonical inflammasome pathway, and that SCGB3A2 may serve as a novel therapeutic to treat cancer, perhaps in combination with immuno and/or targeted therapies.

scholarly journals Prospects for Development of Induced Pluripotent Stem Cell-Derived CAR-Targeted Immunotherapies

2021 ◽  
Vol 70 (1) ◽  
Author(s):  
Roberta Mazza ◽  
John Maher
Keyword(s):  
Immune Cell ◽  
Ex Vivo ◽  
Human Cancer ◽  
Induced Pluripotent Stem Cell ◽  
Solid Tumours ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
Drug Products ◽  
Induced Pluripotent ◽  
Near Future

AbstractTechnologies required to generate induced pluripotent stem cells (iPSC) were first described 15 years ago, providing a strong impetus to the field of regenerative medicine. In parallel, immunotherapy has finally emerged as a clinically meaningful modality of cancer therapy. In particular, impressive efficacy has been achieved in patients with selected haematological malignancies using ex vivo expanded autologous T cells engineered to express chimeric antigen receptors (CARs). While solid tumours account for over 90% of human cancer, they currently are largely refractory to this therapeutic approach. Nonetheless, given the considerable innovation taking place worldwide in the CAR field, it is likely that effective solutions for common solid tumours will emerge in the near future. Such a development will create significant new challenges in the scalable delivery of these complex, costly and individualised therapies. CAR-engineered immune cell products that originate from iPSCs offer the potential to generate unlimited numbers of homogeneous, standardised cell products in which multiple defined gene modification events have been introduced to ensure safety, potency and reproducibility. Here, we review some of the emerging strategies in use to engineer CAR-expressing iPSC-derived drug products.

scholarly journals Deficiency of Ku Induces Host Cell Exploitation in Human Cancer Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Okay Saydam ◽  
Nurten Saydam
Keyword(s):  
Host Cell ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Metastasis ◽  
Human Cancer ◽  
Therapy Resistance ◽  
Host Cells ◽  
Human Cancer Cells ◽  
Parasitic Lifestyle

Cancer metastasis is the major cause of death from cancer (Massague and Obenauf, 2016; Steeg, 2016). The extensive genetic heterogeneity and cellular plasticity of metastatic tumors set a prime barrier for the current cancer treatment protocols (Boumahdi and de Sauvage, 2020). In addition, acquired therapy resistance has become an insurmountable obstacle that abolishes the beneficial effects of numerous anti-cancer regimens (De Angelis et al., 2019; Boumahdi and de Sauvage, 2020). Here we report that deficiency of Ku leads to the exploitation of host cells in human cancer cell line models. We found that, upon conditional deletion of XRCC6 that codes for Ku70, HCT116 human colorectal cancer cells gain a parasitic lifestyle that is characterized by the continuous cycle of host cell exploitation. We also found that DAOY cells, a human medulloblastoma cell line, innately lack nuclear Ku70/Ku86 proteins and utilize the host-cell invasion/exit mechanism for maintenance of their survival, similarly to the Ku70 conditionally-null HCT116 cells. Our study demonstrates that a functional loss of Ku protein promotes an adaptive, opportunistic switch to a parasitic lifestyle in human cancer cells, providing evidence for a previously unknown mechanism of cell survival in response to severe genomic stress. We anticipate that our study will bring a new perspective for understanding the mechanisms of cancer cell evolution, leading to a shift in the current concepts of cancer therapy protocols directed to the prevention of cancer metastasis and therapy resistance.

scholarly journals NK-Cell-Mediated Targeting of Various Solid Tumors Using a B7-H3 Tri-Specific Killer Engager In Vitro and In Vivo

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2659 ◽  
Author(s):  
Daniel A. Vallera ◽  
Soldano Ferrone ◽  
Behiye Kodal ◽  
Peter Hinderlie ◽  
Laura Bendzick ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cell Function ◽  
Nk Cell ◽  
Human Cancer ◽  
Cell Activity ◽  
Antibody Fragment

We improved the bispecific antibody platform that primarily engages natural killer (NK) cells to kill cancer cells through antibody-dependent cellular cytotoxicity (ADCC) by adding IL-15 as a crosslinker that expands and self-sustains the effector NK cell population. The overall goal was to target B7-H3, an established marker predominantly expressed on cancer cells and minimally expressed on normal cells, and prove that it could target cancer cells in vitro and inhibit tumor growth in vivo. The tri-specific killer engager (TriKETM) was assembled by DNA shuffling and ligation using DNA encoding a camelid anti-CD16 antibody fragment, a wild-type IL-15 moiety, and an anti-B7-H3 scFv (clone 376.96). The expressed and purified cam1615B7H3 protein was tested for in vitro NK cell activity against a variety of tumors and in vivo against a tagged human MA-148 ovarian cancer cell line grafted in NSG mice. cam1615B7H3 showed specific NK cell expansion, high killing activity across a range of B7-H3+ carcinomas, and the ability to mediate growth inhibition of aggressive ovarian cancer in vivo. cam1615B7H3 TriKE improves NK cell function, expansion, targeted cytotoxicity against various types of B7-H3-positive human cancer cell lines, and delivers an anti-cancer effect in vivo in a solid tumor setting.

scholarly journals System-Wide Analysis of Protein Acetylation and Ubiquitination Reveals a Diversified Regulation in Human Cancer Cells

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 411 ◽  
Author(s):  
Hiroko Kozuka-Hata ◽  
Aya Kitamura ◽  
Tomoko Hiroki ◽  
Aiko Aizawa ◽  
Kouhei Tsumoto ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Translational Control ◽  
Large Scale ◽  
Human Cancer ◽  
Initiation Factor ◽  
Protein Acetylation ◽  
Human Cancer Cell Lines ◽  
Human Cancer Cells ◽  
Lysine Modification

Post-translational modifications are known to be widely involved in the regulation of various biological processes, through the extensive diversification of each protein function at the cellular network level. In order to unveil the system-wide function of the protein lysine modification in cancer cell signaling, we performed global acetylation and ubiquitination proteome analyses of human cancer cells, based on high-resolution nanoflow liquid chromatography–tandem mass spectrometry, in combination with the efficient biochemical enrichment of target modified peptides. Our large-scale proteomic analysis enabled us to identify more than 5000 kinds of ubiquitinated sites and 1600 kinds of acetylated sites, from representative human cancer cell lines, leading to the identification of approximately 900 novel lysine modification sites in total. Very interestingly, 236 lysine residues derived from 141 proteins were found to be modified with both ubiquitination and acetylation. As a consequence of the subsequent motif extraction analyses, glutamic acid (E) was found to be highly enriched at the position (−1) for the lysine acetylation sites, whereas the same amino acid was relatively dispersed along the neighboring residues of the lysine ubiquitination sites. Our pathway analysis also indicated that the protein translational control pathways, such as the eukaryotic initiation factor 2 (EIF2) and the ubiquitin signaling pathways, were highly enriched in both of the acetylation and ubiquitination proteome data at the network level. This report provides the first integrative description of the protein acetylation and ubiquitination-oriented systematic regulation in human cancer cells.

scholarly journals A Novel and Efficient Approach for Screening Cancer Cell Specific Monoclonal Antibodies

2019 ◽  
Author(s):  
Xin-Hui Pei
Keyword(s):  
Monoclonal Antibodies ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Human Liver ◽  
Human Cancer ◽  
Human Cells ◽  
Specific Antibodies ◽  
Human Cancer Cells ◽  
Normal Human ◽  
Normal Human Cells

AbstractCancer cell specific antibodies are pivotal tools in developing new immunotherapies for treating cancers. However, acquirement of cancer cell specific antibodies is time-consuming and often arduous. To circumvent such a barrier, we developed a novel antibody-screening method that can be used to efficiently produce cancer cell specific antibodies by an ‘antibody filter’ mechanism. First, we used normal human cells to perform the immunization in mice and collected the antisera. Second, we used human cancer cells together with the antisera against normal human cells to immunize another batch of mice. Theoretically, the antisera were able to neutralize the antigens from normal human cells, and therefore specific antigens only expressed in cancer cells could take advantage of the immunization. Third, we screened positive clones that are specific for cancer cells but not normal cells. Using this conceptual method, we successfully obtained 11 monoclonal antibodies that are specific for a human liver cancer cells line (HepG2) but not for a normal human liver cell line (HH). In addition, these clones failed to recognize other human cancer cells originated from different tissues, further highlighting the specificity. Collectively, we provide a novel and effective approach for screening cancer cell specific monoclonal antibodies, which may significantly facilitate the development of new anti-cancer therapeutics.

scholarly journals Antiproliferation effect of sulforaphene isolated from radish (Raphanus sativus L.) seeds on A549 cells

2020 ◽  
Vol 63 (1) ◽  
Author(s):  
Sooyeon Lim ◽  
Jin-Chul Ahn ◽  
Eun Jin Lee ◽  
Jongkee Kim
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
A549 Cells ◽  
Cancer Cell Lines ◽  
Human Cancer Cells ◽  
Induced Apoptosis ◽  
Ht 29 ◽  
A549 Lung

Abstract Sulforaphene (SFE), a major isothiocyanate in radish seeds, is a close chemical relative of sulforaphane (SFA) isolated from broccoli seeds and florets. The anti-proliferative mechanisms of SFA against cancer cells have been well investigated, but little is known about the potential anti-proliferative effects of SFE. In this study, we showed that SFE purified from radish seeds inhibited the growth of six cancer cell lines (A549, CHO, HeLa, Hepa1c1c7, HT-29, and LnCaP), with relative half maximal inhibitory concentration values ranging from 1.37 to 3.31 μg/mL. Among the six cancer cell lines, SFE showed the greatest growth inhibition against A549 lung cancer cells, where it induced apoptosis by changing the levels of poly(ADP-ribose) polymerase and caspase-3, -8, and -9. Our results indicate that SFE from radish seeds may have significant anti-proliferative potency against a broad range of human cancer cells via induction of apoptosis.

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