Lung specific X protein as a novel therapeutic target for lung cancer

Zheng, Xiaohu; Tian, Zhigang; Wei, Haiming

doi:10.1080/2162402x.2015.1052931

Cited by 2 publications

(2 citation statements)

References 10 publications

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“…Tumor cells are not killed directly by a sublethal dose of mitoxantrone treatment, but most of these cells enter “premature senescence”, which is strengthened further even after drug withdrawal. Attempting to survive under this drug-induced stress, tumor cells express more LUNX on their plasma membrane, the overexpression of which we showed previously to promote the migration and proliferation of lung cancer cells [ 43 ]. Targeting surface LUNX via anti-LUNX antibody at this time more efficiently suppresses the survival of these LUNX-high-expressing senescent tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Immunogenic senescence sensitizes lung cancer to LUNX-targeting therapy

Jiao

Zheng

et al. 2021

Cancer Immunol Immunother

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The higher immunogenicity of tumors usually predicts favorable therapeutic responses. Tumor antigens dominate the immunogenic character within tumors. We investigated if there was a targetable tumor antigen during immunogenic chemotherapy within lung cancer. Chemotherapy-induced immunogenic senescence was demonstrated using a multi-marker, three-step workflow, and RNA-sequencing data. The ability of anti-lung-specific X protein (LUNX) antibody to suppress the survival of senescent lung cancer cells was evaluated in vitro and in vivo using real-time cytotoxicity analysis and xenograft mouse models, respectively. The induction of cellular senescence by immunogenic chemotherapy boosted cell-surface shuttling of LUNX and enhanced the immunogenic features of senescent tumor cells, which sensitized lung cancer cells to anti-LUNX antibody-mediated therapy and contributed to tumor suppression. The immunogenic senescence-mediated anti-tumor response was triggered by the direct action of antibody on tumor cells, strengthened by natural-killer cells through an antibody-dependent cell-mediated cytotoxicity response, and ultimately, led to tumor control. Our findings suggest that LUNX is a lung cancer targetable-immunogenic antigen. The proportion of lung cancers responding to LUNX-targeting therapy could be expanded substantially by immunogenic chemotherapy that induces senescence-associated translocation of LUNX to the plasma membrane.

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Section: Discussionmentioning

confidence: 99%

Immunogenic senescence sensitizes lung cancer to LUNX-targeting therapy

Jiao

Zheng

et al. 2021

Cancer Immunol Immunother

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“…22 Previously, we demonstrated that LunX antibody-based therapy could suppress the growth, metastasis, and invasion of LunX-positive tumor cells by inducing downregulation of expression of LunX and blockade of the downstream pathways of LunX. 23,24 In another study by our research team using mice, we showed that treatment with LunX antibody led to no cases of sudden death, pulmonary inflammation, or lung injury, which demonstrated an absence of toxic side effects of LunX antibody. 25 In the present study, we searched for a target antigen specific for lung cancer that has high expression among NSCLC patients.…”

Section: Introductionmentioning

confidence: 94%

LunX-CAR T Cells as a Targeted Therapy for Non-Small Cell Lung Cancer

Zheng

Jiao

et al. 2020

Molecular Therapy - Oncolytics

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Non-small cell lung cancer (NSCLC) carries a high mortality, and efficacious therapy is lacking. Therapy using chimeric antigen receptor (CAR) T cells has been used efficaciously against hematologic malignancies, but the curative effect against solid tumors is not satisfactory. A lack of antigen targets is one of the main reasons for this limited efficacy. Previously, we showed that lung-specific X (LUNX; also known as BPIFA1, PLUNC, and SPLUNC1) is overexpressed in lung cancer cells. Here, we constructed a CAR-T-cell-based strategy to target LunX (CAR LunX T cells). CAR T cells were developed so that, upon specific recognition of LunX, they secreted cytokines and killed LunX-positive NSCLC cells. In vitro, CAR LunX T cells displayed enhanced toxicity toward NSCLC lines and production of cytokines and showed specific LunX-dependent recognition of NSCLC cells. Adoptive transfer of CAR LunX T cells induced regression of established metastatic lung cancer xenografts and prolonged survival. CAR LunX T cells could infiltrate into the tumor. Also, we constructed a patient-derived xenograft model of lung cancer. After therapy with CAR LunX T cells, tumor growth was suppressed, and survival was prolonged significantly. Together, our findings offer preclinical evidence of the immunotherapeutic targeting of LunX as a strategy to treat NSCLC.

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Lung specific X protein as a novel therapeutic target for lung cancer

Cited by 2 publications

References 10 publications

Immunogenic senescence sensitizes lung cancer to LUNX-targeting therapy

Immunogenic senescence sensitizes lung cancer to LUNX-targeting therapy

LunX-CAR T Cells as a Targeted Therapy for Non-Small Cell Lung Cancer

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