The inability of adoptive immunotherapy to eradicate tumor cells in radiation-induced chimeric mice: The possible down-regulation of intratumor immune amplification

Retraction of ‘Down-regulation of the radiation-induced pEGFRThr654 mediated activation of DNA-PK by Cetuximab in cervical cancer cells’ by Yunxiang Qi et al., RSC Adv., 2020, 10, 1132–1141, DOI: 10.1039/C9RA04962B.

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CBIO-11. NOVEL THERAPY TO TARGET PR-RECURRENT GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.071 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii17-ii18

Author(s):

Masum Rahman ◽

Ian E Olson ◽

Rehan Saber ◽

Jibo Zhang ◽

Lucas P Carlstrom ◽

...

Keyword(s):

Tumor Cells ◽

Tumor Recurrence ◽

Primary Brain Tumor ◽

Differential Sensitivity ◽

Proliferating Cells ◽

Novel Therapy ◽

Conventional Radiation ◽

Long Time ◽

Radiation Induced

Abstract BACKGROUND Glioblastoma is a fatal infiltrative primary brain tumor, and standard care includes maximal safe surgical resection followed by radiation and Temozolomide (TMZ). Therapy-resistant residual cells persist in a latent state a long time before inevitable recurrence. Conventional radiation and Temozolomide (TMZ) treatment cause oxidative stress and DNA damage resulting senescent-like state of cell-cycle arrest. However, increasing evidence demonstrates escaping senescence leads to tumor recurrence. Thus, the ablation of senescent tumor cells after chemoradiation may be an avenue to limit tumor recurrence. METHODS 100uM TMZ for 7days or 10-20Gy radiation (cesium gamma radiator) was used for senescence induction in human glioblastoma in vitro and confirmed by SA-Beta gal staining and PCR. Replication arrest assessed by automated quantification of cellular confluence (Thermo Scientific Series 8000 WJ Incubator). We evaluated the IC50 for several senolytics targeting multiple SCAPs, including Dasatinib, Quercetin, AMG-232, Fisetin, Onalespib, Navitoclax, and A1331852, and in senescent vs. proliferating cells. RESULTS Among the senolytic tested, the Bcl-XL inhibitors A1331852 and Navitoclax both shown senolytic effect by selectively killing radiated, senescent tumor cells at lower concentrations as compared to 0Gy treated non-senescent cells. Across 12 GBM cell lines, IC50 for senescent cells was 6–500 times lower than non-senescent GBM(p< 0.005). Such differential sensitivity to Bcl-XL inhibition after radiation has also observed by BCL-XL knockdown in radiated glioma. CONCLUSION These findings suggest the potential to harness radiation-induced biology to ablate surviving quiescent cells and demonstrate Bcl-XL dependency as a potential vulnerability of surviving tumor cells after exposure to chemoradiation.

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150 GAIA-102: a new class off-the-shelf allogeneic NK-like cells that can eliminate solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0150 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A163-A163

Author(s):

Yui Harada ◽

Yoshikazu Yonemitsu

Keyword(s):

Nk Cells ◽

Solid Tumors ◽

Tumor Cells ◽

Adoptive Immunotherapy ◽

Nk Cell ◽

Peritoneal Dissemination ◽

Checkpoint Inhibitors ◽

Antitumor Effects ◽

Car T

BackgroundCancer immunotherapy has been established as a new therapeutic category since the recent success of immune checkpoint inhibitors and a type of adoptive immunotherapy, namely chimeric antigen receptor-modified T cells (CAR-T). Although CAR-T demonstrated impressive clinical results, serious adverse effects (cytokine storm and on-target off-tumor toxicity) and undefined efficacy on solid tumors are important issues to be solved. We’ve developed a cutting-edge, simple, and feeder-free method to generate highly activated and expanded human NK cells from peripheral blood (US9404083, PCT/JP2019/012744, PCT/JP2020/012386), and have been conducting further investigation why our new type of NK cells, named as GAIA-102, are so effective to kill malignant cells.MethodsCryopreserved PBMCs purchased from vendors were mixed and processed by using LOVO and CliniMACS® Prodigy (automated/closed systems). CD3+ and CD34+ cells were depleted, and the cells were cultured with high concentration of hIL-2 and 5% UltraGRO® for 14 days in our original closed system. Then, we confirmed the expression of surface markers, CD107a mobilization and cell-mediated cytotoxicity against various tumor cells and normal cells with or without monoclonal antibody drugs in vitro and antitumor effects against peritoneal dissemination model using SKOV3 in vivo.ResultsImportantly, we’ve found that our GAIA-102 exhibited CD3-/CD56bright/CD57- immature phenotype that could kill various tumor cells efficiently from various origins, including Raji cells that was highly resistant to NK cell killing. More importantly, massive accumulation, retention, infiltration and sphere destruction by GAIA-102 were affected neither by myeloid-derived suppressor cells nor regulatory T-lymphocytes. GAIA-102 was also effective in vivo to murine model of peritoneal dissemination of human ovarian cancer; thus, these findings indicate that GAIA-102 has a potential to be an ‘upward compatible’ modality over CAR-T strategy, and would be a new and promising candidate for adoptive immunotherapy against solid tumors.ConclusionsWe now just started GMP/GCTP production of this new and powerful NK cells and first-in-human clinical trials in use of GAIA-102 will be initiated on 2021.Ethics ApprovalThe animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee of Kyushu University (approval nos. A30-234-0 and A30-359-0).

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Icariin induces apoptosis in mouse MLTC-10 Leydig tumor cells through activation of the mitochondrial pathway and down-regulation of the expression of piwil4

International Journal of Oncology ◽

10.3892/ijo.2011.1086 ◽

2011 ◽

Cited By ~ 3

Author(s):

Yi Xie

Keyword(s):

Tumor Cells ◽

Mitochondrial Pathway ◽

Down Regulation ◽

Leydig Tumor Cells

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Down-Regulation of Ceramide Production Abrogates Ionizing Radiation-Induced CytochromecRelease and Apoptosis

Molecular Pharmacology ◽

10.1124/mol.57.4.792 ◽

2000 ◽

Vol 57 (4) ◽

pp. 792-796 ◽

Cited By ~ 25

Author(s):

Steven J. Chmura ◽

Edwardine Nodzenski ◽

Surender Kharbanda ◽

Pramod Pandey ◽

Jose Quintans ◽

...

Keyword(s):

Ionizing Radiation ◽

Down Regulation ◽

Radiation Induced ◽

Ceramide Production

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Inhibition of Rac1 attenuates radiation-induced lung injury while suppresses lung tumor in mice

Cell Death Discovery ◽

10.1038/s41420-021-00791-8 ◽

2022 ◽

Vol 8 (1) ◽

Author(s):

Ni An ◽

Zhenjie Li ◽

Xiaodi Yan ◽

Hainan Zhao ◽

Yajie Yang ◽

...

Keyword(s):

Ionizing Radiation ◽

Lung Injury ◽

Mouse Model ◽

Tumor Cells ◽

Nuclear Translocation ◽

Lung Tumor ◽

Lung Epithelial Cells ◽

Normal Lung ◽

Limiting Factor ◽

Radiation Induced

AbstractThe lung is one of the most sensitive tissues to ionizing radiation, thus, radiation-induced lung injury (RILI) stays a key dose-limiting factor of thoracic radiotherapy. However, there is still little progress in the effective treatment of RILI. Ras-related C3 botulinum toxin substrate1, Rac1, is a small guanosine triphosphatases involved in oxidative stress and apoptosis. Thus, Rac1 may be an important molecule that mediates radiation damage, inhibition of which may produce a protective effect on RILI. By establishing a mouse model of radiation-induced lung injury and orthotopic lung tumor-bearing mouse model, we detected the role of Rac1 inhibition in the protection of RILI and suppression of lung tumor. The results showed that ionizing radiation induces the nuclear translocation of Rac1, the latter then promotes nuclear translocation of P53 and prolongs the residence time of p53 in the nucleus, thereby promoting the transcription of Trp53inp1 which mediates p53-dependent apoptosis. Inhibition of Rac1 significantly reduce the apoptosis of normal lung epithelial cells, thereby effectively alleviating RILI. On the other hand, inhibition of Rac1 could also significantly inhibit the growth of lung tumor, increase the radiation sensitivity of tumor cells. These differential effects of Rac1 inhibition were related to the mutation and overexpression of Rac1 in tumor cells.

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Radiation Induced Upregulation of DNA Sensing Pathways is Cell-Type Dependent and Can Mediate the Off-Target Effects

Cancers ◽

10.3390/cancers12113365 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3365

Author(s):

Tanja Jesenko ◽

Masa Bosnjak ◽

Bostjan Markelc ◽

Gregor Sersa ◽

Katarina Znidar ◽

...

Keyword(s):

Tumor Cells ◽

Checkpoint Inhibitors ◽

Cell Types ◽

Immunofluorescent Staining ◽

Dna Sensing ◽

Radiation Induced ◽

Underlying Mechanisms ◽

Sting Pathway ◽

Abscopal Effects ◽

Target Effects

Irradiation of tumors generates danger signals and inflammatory cytokines that promote the off-target bystander and abscopal effects, evident especially when radiotherapy is administered in combination with the immune checkpoint inhibitors (ICI). The underlying mechanisms are not fully understood; however, cGAS-STING pathway was recognized as the main mediator. In our study, we demonstrate by immunofluorescent staining that tumor cells as well as macrophages, cell types abundant in the tumor microenvironmeent (TME) accumulate DNA in their cytosol soon after irradiation. This accumulation activated several distinct DNA sensing pathways, most prominently activated DNA sensors being DDX60, DAI, and p204 in tumor cells and DDX60, DAI, p204, and RIG-I in macrophages as determined by PCR and immunofluorescence imaging studies. This was accompanied by increased expression of cytokines evaluated by flow cytometry, TNFα, and IFNβ in tumor cells and IL1β and IFNβ in macrophages, which can alter the TME and mediate off-target effects (bystander or abscopal effects). These results give insight into the mechanisms involved in the stimulation of antitumor immunity by radiation.

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