Our lab focuses on novel approaches to improve the impact of immunotherapy on malignant pleural mesothelioma and non-small cell lung cancer. We have developed clinically translatable tumor pre-treatment strategies that favor immunogenicity through cancer vascular modulation to improve the impact of immune checkpoint inhibitors. We are also interested in a better comprehension of the lung cancer vascular characteristics that favor an immune microenvironment that promotes/prevents tumor dissemination to the brain. We have developed a unique thoracic window model that allows intravital imaging of orthotopic tumors (lung cancer and mesothelioma) and their compartments via two-photon laser scanning microscopy. Our research aims to establish pre-clinical evidence for treatment combinations that are then translatable to the clinics. ...
Changes of interstitial fluid pressure and blood flow in tumors after low dose photodynamic therapy (L-PDT)
To better understand the mechanism responsible for enhanced drug distribution by L-PDT, we assessed the real time changes of tumor/lung interstitial fluid pressure (IFP) and tumor blood flow (TBF) in mouse models of malignant pleural mesothelioma (MPM), lung adenocarcinoma, and pleural sarcomas in rodents before and during L-PDT. We found that photo-induction caused a significant decrease in IFP in all tumor models compared to controls while keeping TBF stable. These observations suggest photo-induction related tumor vasculature alterations with enhancement in convection between the intra- and extravascular spaces which improves drug distribution. The changes in IFP and TBF were similar to those observed with low-dose anti-angiogenic therapy (vascular normalization). Interestingly, no changes in IFP, TBF or drug distribution was observed in adjacent normal lung tissue equally submitted to photo-induction.
L-PDT causes pericyte activation and increases tumor vascular stability
To further understand how L-PDT was stabilizing tumor vessels, we performed in vitro endothelial/pericyte co-culture assays where cells were exposed to L-PDT. We found that L-PDT caused a specific cytoskeletal remodeling in pericytes through RhoA, MLC and FAK. This was confirmed in MPM tumors in mice, where the same pathways, as well as enhanced pericyte coverage of endothelial cells and vascular stabilization after L-PDT, were detected.
Impact of L-PDT on the immune response against MPM and on the combination with immune checkpoint inhibitors.
Given the favorable impact of L-PDT on drug distribution but also its impact on the immune response, we tested whether L-PDT could enhance the immune response against MPM in a murine immunocompetent model and assessed how L-PDT affected subsequent immune checkpoint inhibition therapy. FACS analysis of L-PDT treated MPM (AE17 tumors grown in C57B6 mice) showed that a single PDT treatment enhanced the ratio of CD8+ cells over CD4 helper cells and increased the activity of antigen presenting cells (macrophages and dendritic cells) at day 7. While this had no impact on tumor growth, the combination of L-PDT with anti-CTLA-4 immune checkpoint therapy controlled MPM tumor growth significantly better than controls. Interestingly, the combination of L-PDT with anti-CTLA-4 caused a complete tumor regression in 30% of animals. Finally, enhanced E-Selectin expression, a molecule involved in leucocyte diapedesis, was observed at the endothelial level
Therapeutic reconditioning of damaged lungs by transient heat stress during ex-vivo lung perfusion.
Ojanguren A, Parapanov R, Debonneville A, (...), Perentes JY, Krueger T, Liaudet L
American journal of transplantation – 2023 May 20
Local control and short-term outcomes after video-assisted thoracoscopic surgery segmentectomy versus lobectomy for pT1c pN0 non-small-cell lung cancer.
Forster C, Abdelnour-Berchtold E, Bédat B, (...), Karenovics W, Krueger T, Gonzalez M
Interdisciplinary cardiovascular and thoracic surgery – 2023 Feb 6
CT-Derived Sarcopenia and Outcomes after Thoracoscopic Pulmonary Resection for Non-Small Cell Lung Cancer.
Hasenauer A, Forster C, Hungerbühler J, (...), Krueger T, Becce F, Gonzalez M
Cancers – 2023 Jan 27
Effectiveness of rib fixation compared to pain medication alone on pain control in patients with uncomplicated rib fractures: study protocol of a pragmatic multicenter randomized controlled trial-the PAROS study (Pain After Rib OSteosynthesis).
Perentes JY, Christodoulou M, Abdelnour-Berchtold E, (...), Triponez F, Terrier P, Bédat B
Trials – 2022 Sep 2
Is faster better? Impact of operative time on postoperative outcomes after VATS anatomical pulmonary resection.
Forster C, Hasenauer A, Perentes JY, (...), Zellweger M, Krueger T, Gonzalez M
Journal of thoracic disease – 2022 Jun
Prognostic influence of tumor microenvironment after hypofractionated radiation and surgery for mesothelioma.
de Perrot M, Wu L, Cabanero M, (...), Keshavjee S, Tsao MS, Cho BCJ
The Journal of thoracic and cardiovascular surgery – 2019 Nov 13
Comparison of postoperative complications between segmentectomy and lobectomy by video-assisted thoracic surgery: a multicenter study.
Bédat B, Abdelnour-Berchtold E, Perneger T, (...), Triponez F, Karenovics W, Gonzalez M
Journal of cardiothoracic surgery – 2019 Nov 7
An enhanced recovery after surgery program for video-assisted thoracoscopic surgery anatomical lung resections is cost-effective.
Gonzalez M, Abdelnour-Berchtold E, Perentes JY, (...), Ris HB, Krueger T, Gronchi F
Journal of thoracic disease – 2018 Oct
Surgical treatment of pulmonary metastasis in colorectal cancer patients: Current practice and results.
Zellweger M, Abdelnour-Berchtold E, Krueger T, (...), Ris HB, Perentes JY, Gonzalez M
Critical reviews in oncology/hematology – 2018 Jun 4
Extracorporeal support for pulmonary resection: current indications and results.
Rosskopfova P, Perentes JY, Ris HB, (...), Gronchi F, Krueger T, Gonzalez M
World journal of surgical oncology – 2016 Feb 2
Pre-operative localization of solitary pulmonary nodules with computed tomography-guided hook wire: report of 181 patients.
Hanauer M, Perentes JY, Krueger T, (...), Bize P, Schmidt S, Gonzalez M
Journal of cardiothoracic surgery – 2016 Jan 16
Thoracoscopic resection of pulmonary metastasis: current practice and results.
Perentes JY, Krueger T, Lovis A, Ris HB, Gonzalez M
Critical reviews in oncology/hematology – 2015 Feb 17
Vacuum-assisted closure device for the management of infected postpneumonectomy chest cavities.
Perentes JY, Abdelnour-Berchtold E, Blatter J, (...), Ris HB, Krueger T, Gonzalez M
The Journal of thoracic and cardiovascular surgery – 2014 Oct 14
Low-Dose Vascular Photodynamic Therapy Decreases Tumor Interstitial Fluid Pressure, which Promotes Liposomal Doxorubicin Distribution in a Murine Sarcoma Metastasis Model.
Perentes JY, Wang Y, Wang X, (...), Peters S, Ris HB, Krueger T
Translational oncology – 2014 May 13
Cancer cell-associated MT1-MMP promotes blood vessel invasion and distant metastasis in triple-negative mammary tumors.
Perentes JY, Kirkpatrick ND, Nagano S, (...), Munn LL, Jain RK, Boucher Y
Cancer research – 2011 May 13
Vacuum-assisted closure device: a useful tool in the management of severe intrathoracic infections.
Saadi A, Perentes JY, Gonzalez M, (...), Demartines N, Ris HB, Krueger T
The Annals of thoracic surgery – 2011 Feb 26
Blockade of VEGFR2 and not VEGFR1 can limit diet-induced fat tissue expansion: role of local versus bone marrow-derived endothelial cells.
Tam J, Duda DG, Perentes JY, (...), Quadri RS, Fukumura D, Jain RK
PloS one – 2009 Mar 31
In vivo imaging of extracellular matrix remodeling by tumor-associated fibroblasts.
Perentes JY, McKee TD, Ley CD, (...), Munn LL, Jain RK, Boucher Y
Nature methods – 2009 Jan 18
Cancer cell death enhances the penetration and efficacy of oncolytic herpes simplex virus in tumors.
Nagano S, Perentes JY, Jain RK, Boucher Y
Cancer research – 2008 May 15
Evidence for incorporation of bone marrow-derived endothelial cells into perfused blood vessels in tumors.
Duda DG, Cohen KS, Kozin SV, (...), Fukumura D, Scadden DT, Jain RK
Blood – 2005 Dec 8