☆ 4.7 Article

Combined IFN-γ-Endostatin Gene Therapy and Radiotherapy Attenuates Primary Breast Tumor Growth and Lung Metastases via Enhanced CTL and NK Cell Activation and Attenuated Tumor Angiogenesis in a Murine Model

ANNALS OF SURGICAL ONCOLOGY (2009)

Journal

ANNALS OF SURGICAL ONCOLOGY

Volume 16, Issue 5, Pages 1403-1411

Publisher

SPRINGER

DOI: 10.1245/s10434-009-0343-6

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Abstract

Gene-radiotherapy, a combination of gene therapy and radiotherapy, is a new paradigm for cancer treatment, with the potential to simultaneously improve local and systemic breast cancer control. The aim of this study was to evaluate antitumor effect of interferon (IFN)-gamma-endostatin-based gene-radiotherapy in a murine metastatic breast tumor model, and to elucidate possible mechanisms involved. Murine mammary adenocarcinoma 4T1 cells transfected with pEgr-IFN-gamma and pEgr-endostatin plasmids were irradiated (2-20 Gy). IFN-gamma and endostatin levels in the culture supernatants were measured. In vivo female BALB/c mice were inoculated with 1 x 10(5) 4T1 cells by mammary fat pad injection and divided into control, empty vector, gene therapy (pEgr-IFN-gamma and pEgr-endostatin), radiotherapy, and combined gene-radiotherapy groups. Tumor growth, tumor/body weight ratio, lung metastases, and survival of the tumor-bearing mice were observed. Splenic cytotoxic T-lymphocyte (CTL) and natural killer (NK) cell activity and intratumor microvessel density were also assessed. Irradiation significantly enhanced IFN-gamma and endostatin secretion from the transfected 4T1 cells. In vivo mice that received combined gene-radiotherapy showed maximal attenuation in tumor growth rate and lung metastases with increased survival compared with mice that received gene therapy or radiotherapy alone. This was associated with significantly enhanced CTL and NK cell activity and reduced intratumor microvessel density. These results demonstrate that IFN-gamma-endostatin-based gene-radiotherapy provide a potent antitumor effect in a murine metastatic breast tumor model, which may relate to IFN-gamma-stimulated CTL and NK cell activation, and endostatin-induced antiangiogenic activity. Thus, gene-radiotherapy may represent a useful addition to neoadjuvant management of locally advanced breast cancer.

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Attenuated Cytokine-Induced Memory-Like Natural Killer Cell Responses to Mycobacterium tuberculosis in Tuberculosis Patients

Chen Liang, Shanshan Li, Jinfeng Yuan, Yanhua Song, Weicong Ren, Wei Wang, Yuanyuan Shang, Shenjie Tang, Yu Pang

Summary: This study aimed to investigate the phenotype, proliferation and functional alterations of cytokine-induced memory-like natural killer (CIML NK) cells from healthy subjects and TB patients, and assessed the efficacy of CIML NK cells in response to H37Rv-infected U937 cells in vitro. CIML NK cells from healthy individuals showed enhanced IFN-gamma secretion and boosted anti-MTB activity in vitro, which from TB patients show impaired IFN-gamma production and no enhanced anti-MTB activity compared to those from healthy donors. These results open up new possibilities for NK cell-based anti-tuberculosis immunotherapeutic strategies.

INFECTION AND DRUG RESISTANCE (2023)