Immunization against ROS1 by DNA Electroporation Impairs K-Ras-Driven Lung Adenocarcinomas ​.

Federica Riccardo,Marco Volante,Maddalena Arigoni,Laura Conti,Angela Petito,Elena Quaglino,Stefania Izzo,Mauro Papotti,Irene Fiore Merighi,Dario Livio Longo,Giuseppina Barutello,Lidia Tarone,Chiara Musiu,Federica Cavallo

doi:10.3390/vaccines8020166

Immunization against ROS1 by DNA Electroporation Impairs K-Ras-Driven Lung Adenocarcinomas .

Federica Riccardo, Marco Volante + Show 12 more

Open Access

https://doi.org/10.3390/vaccines8020166

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Abstract

Non-small cell lung cancer (NSCLC) is still the leading cause of cancer death worldwide. Despite the introduction of tyrosine kinase inhibitors and immunotherapeutic approaches, there is still an urgent need for novel strategies to improve patient survival. ROS1, a tyrosine kinase receptor endowed with oncoantigen features, is activated by chromosomal rearrangement or overexpression in NSCLC and in several tumor histotypes. In this work, we have exploited transgenic mice harboring the activated K-Ras oncogene (K-RasG12D) that spontaneously develop metastatic NSCLC as a preclinical model to test the efficacy of ROS1 immune targeting. Indeed, qPCR and immunohistochemical analyses revealed ROS1 overexpression in the autochthonous primary tumors and extrathoracic metastases developed by K-RasG12D mice and in a derived transplantable cell line. As proof of concept, we have evaluated the effects of the intramuscular electroporation (electrovaccination) of plasmids coding for mouse- and human-ROS1 on the progression of these NSCLC models. A significant increase in survival was observed in ROS1-electrovaccinated mice challenged with the transplantable cell line. It is worth noting that tumors were completely rejected, and immune memory was achieved, albeit only in a few mice. Most importantly, ROS1 electrovaccination was also found to be effective in slowing the development of autochthonous NSCLC in K-RasG12D mice.

Highlights

Lung cancer is still one of the major unresolved issues in the oncology panorama [1]
We have focused on the c-ros oncogene 1 receptor tyrosine kinase (ROS1), an orphan tyrosine kinase receptor whose aberrant activation has been implicated with enhanced tumor cell growth, proliferation, metastasization, and resistance to chemotherapy [25,26,27]
ROS1-positive Non-small cell lung cancer (NSCLC), we exploited transgenic mice that harbor a latent oncogenic K-Ras allele, at the endogenous locus, that is capable of spontaneous activation in vivo, due to an activating mutation at codon 12 (K-RasG12D mice). These mice spontaneously develop NSCLC with 100% of penetrance [70]. We demonstrated that these mice are a reliable translational model for the study of human NSCLC and for investigating the effects of ROS1 targeting, as ROS1 is expressed at all stages of NSCLC progression

Summary

Introduction

Lung cancer is still one of the major unresolved issues in the oncology panorama [1]. Around 80%–85% of lung cancer cases can be classified as non-small cell lung cancer (NSCLC) [2,3]. The best option for long-term survival is surgery when NSCLC is diagnosed in its early stages and is resectable [4,5,6]. The five-year survival is poor even in this case, there is little improvement if patients are treated with neoadjuvant and/or adjuvant chemotherapy [7,8,9,10]. Instead, when NSCLC is diagnosed in advanced or metastatic stages, which occurs in more than 70% of patients, a dramatically worse prognosis is observed, with a 5-year survival of less than 10% when using conventional therapeutic options, including a combination of chemotherapy and radiotherapy [5,11].

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