Solórzano-Rendón, J.L. (José Luis)
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- Intercellular adhesion molecule-1 and vascular cell adhesion molecule are induced by ionizing radiation on lymphatic endothelium(Elsevier, 2016) Etxeberria, I. (Iñaki); Rouzaut, A. (Ana); Rodriguez, I. (Inmaculada); Rodriguez-Ruiz, M.E. (María Esperanza); Aristu-Mendioroz, J.J. (José Javier); Barbes-Fernandez, B. (Benigno); Garasa, S. (Saray); Yanguas, A. (Alba); Halin, C. (Cornelia); Melero, I. (Ignacio); Solórzano-Rendón, J.L. (José Luis); Teijeira, A. (Álvaro)Purpose/Objectives The goal of this study was to assess the effects of ionizing radiation on the expression of the integrin ligands ICAM-1 and VCAM that control leucocyte transit by lymphatic endothelial cells. Materials/Methods Confluent monolayers of primary human lymphatic endothelial cells (LEC) were irradiated with single dose of 2, 5, 10 or 20 Gy, with 6 MeV-x-rays using a Linear-Accelerator. ICAM-1 and VCAM expression was determined by flow cytometry. Human tissue specimens received a single dose of 20 Gy with 15 MeV-x-rays. MC38, B16-OVA or B16-VEGF-C tumors grown in C57BL/6 mice were irradiated with single dose of 20Gy using a Linear-Accelerator fitted with a 10mm Radiosurgery collimator. Clinical samples were obtained from patients previous and 4 weeks after complete standard radiotherapy. ICAM-1 and VCAM expression was detected in all tissue specimens by confocal microscopy. To understand the role of TGFβ in this process anti-TGFβ blocking mAb were injected i.p. 30min before radiotherapy. Cell adhesion to irradiated LEC was analyzed in adhesion experiments performed in the presence or in the absence of anti- TGFβ and /or anti-ICAM1 blocking mAb. Results We demonstrate that lymphatic endothelial cells in tumor samples experience induction of surface ICAM-1 and VCAM when exposed to ionizing radiation in a dose- and time-dependent manner. These effects can be recapitulated in cultured LEC, and are in part mediated by TGFβ. These data are consistent with increases in ICAM-1 and VCAM expression on LYVE-1+ endothelial cells in freshly explanted human tumor tissue and in mouse transplanted tumors after radiotherapy. Finally, ICAM-1 and VCAM expression accounts for enhanced adherence of human T lymphocytes to irradiated LEC. Conclusion Our results show induction of ICAM-1 and VCAM on LVs in irradiated lesions and offer a starting point for elucidating the biological and therapeutic implications of targeting leukocyte traffic in combination to immunotherapy.
- YES1 is a druggable oncogenic target in SCLC(Elsevier, 2022) Redín, E. (Esther); Garrido-Martín, E. (Eva); Valencia, K. (Karmele); Redrado, M. (Miriam); Solórzano-Rendón, J.L. (José Luis); Carias, R. (Rafael); Echepare, M. (Mirari); Expósito, F. (Francisco); Serrano-Tejero, D. (Diego); Ferrer, I. (Irene); Nunez-Buiza, A. (Angel); Garmendia, I. (Irati); García-Pedrero, J.M. (Juana M.); Gurpide, A. (Alfonso); Paz-Ares, L. (Luis); Politi, K. (Katerina); Montuenga-Badia, L.M. (Luis M.); Calvo-González, A. (Alfonso)Introduction: SCLC is an extremely aggressive subtype of lung cancer without approved targeted therapies. Here we identified YES1 as a novel targetable oncogene driving SCLC maintenance and metastasis. Methods: Association between YES1 levels and prognosis was evaluated in SCLC clinical samples. In vitro functional experiments for proliferation, apoptosis, cell cycle, and cytotoxicity were performed. Genetic and pharmacologic inhibition of YES1 was evaluated in vivo in cell- and patientderived xenografts and metastasis. YES1 levels were evaluated in mouse and patient plasma-derived exosomes. Results: Overexpression or gain/amplification of YES1 was identified in 31% and 26% of cases, respectively, across molecular subgroups, and was found as an independent predictor of poor prognosis. Genetic depletion of YES1 dramatically reduced cell proliferation, three-dimensional organoid formation, tumor growth, and distant metastasis, leading to extensive apoptosis and tumor regressions. Mechanistically, YES1-inhibited cells revealed alterations in the replisome and DNA repair processes, that conferred sensitivity to irradiation. Pharmacologic blockade with the novel YES1 inhibitor CH6953755 or dasatinib induced marked antitumor activity in organoid models and cell- and patient-derived xenografts. YES1 protein was detected in plasma exosomes from patients and mouse models, with levels matching those of tumors, suggesting that circulating YES1 could represent a biomarker for patient selection/ monitoring. Conclusions: Our results provide evidence that YES1 is a new druggable oncogenic target and biomarker to advance the clinical management of a subpopulation of patients with SCLC.
- PTEN loss confers resistance to anti-PD-1 therapy in non-small cell lung cancer by increasing tumor infiltration of regulatory T cells(American Association for Cancer Research, 2023) Expósito, F. (Francisco); Redrado, M. (Miriam); Houry, M. (Maeva); Hastings, K. (Katherine); Molero, M. (Magdalena); Lozano-Moreda, T. (Teresa); Solórzano-Rendón, J.L. (José Luis); Sanz, J. (Julián); Adradas, V. (Vera); Amat, R. (Ramon); Redín, E. (Esther); Leon, S. (Sergio); Legarra, N. (Naroa); Garcia, J. (Javier); Serrano-Tejero, D. (Diego); Valencia, K. (Karmele); Robles-Oteiza, C. (Camila); Foggetti, G. (Giorgia); Otegui, N. (Nerea); Felip, E. (Enriqueta); Lasarte, J.J. (Juan José); Paz-Ares, L. (Luis); Zugazagoitia, J. (Jon); Politi, K. (Katerina); Montuenga-Badia, L.M. (Luis M.); Calvo-González, A. (Alfonso)Immunotherapy resistance in non-small cell lung cancer (NSCLC) may be mediated by an immunosuppressive microenvironment, which can be shaped by the mutational landscape of the tumor. Here, we observed genetic alterations in the PTEN/PI3K/AKT/mTOR pathway and/or loss of PTEN expression in >25% of patients with NSCLC, with higher frequency in lung squamous carcinomas (LUSC). Patients with PTEN-low tumors had higher levels of PD-L1 and PD-L2 and showed worse progression-free survival when treated with immunotherapy. Development of a Pten-null LUSC mouse model revealed that tumors with PTEN loss were refractory to antiprogrammed cell death protein 1 (anti-PD-1), highly metastatic and fibrotic, and secreted TGFβ/CXCL10 to promote conversion of CD4+ lymphocytes into regulatory T cells (Treg). Human and mouse PTEN-low tumors were enriched in Tregs and expressed higher levels of immunosuppressive genes. Importantly, treatment of mice bearing Pten-null tumors with TLR agonists and anti-TGFβ antibody aimed to alter this immunosuppressive microenvironment and led to tumor rejection and immunologic memory in 100% of mice. These results demonstrate that lack of PTEN causes immunotherapy resistance in LUSCs by establishing an immunosuppressive tumor microenvironment that can be reversed therapeutically. Significance: PTEN loss leads to the development of an immunosuppressive microenvironment in lung cancer that confers resistance to anti-PD-1 therapy, which can be overcome by targeting PTEN loss-mediated immunosuppression.
- A novel [89Zr]-anti-PD-1-PET-CT to assess response to PD-1/PD-L1 blockade in lung cancer(2023) Gil-Bazo, I. (Ignacio); Francisco-Cruz, A. (Alejandro); Ecay-Ilzarbe, M. (Margarita); Sandiego, S. (Sergio); Puyalto, A. (Ander); Peñuelas-Sanchez, I. (Ivan); Simón-Martínez, J.A. (Jon Ander); NO USAR Collantes-Martínez, M. (María); Vilalta-Lacarra, A. (Anna); Rodríguez-Remírez, M. (M.); Solórzano-Rendón, J.L. (José Luis); Iribarren, F. (Fabiola); Lopez, I. (Inés); Calvo-González, A. (Alfonso); Ajona, D. (Daniel)Background: Harnessing the anti-tumor immune system response by targeting the program cell death protein (PD-1) and program cell death ligand protein (PD-L1) axis has been a major breakthrough in non-small cell lung cancer (NSCLC) therapy. Nonetheless, conventional imaging tools cannot accurately assess response in immunotherapy-treated patients. Using a lung cancer syngeneic mouse model responder to immunotherapy, we aimed to demonstrate that [89Zr]-anti-PD-1 immuno-PET is a safe and feasible imaging modality to assess the response to PD-1/PD-L1 blockade in NSCLC. Materials and methods: A syngeneic mouse model responder to anti-PD-1 therapy was used. Tumor growth and response to PD-1 blockade were monitored by conventional 2-deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG) PET scans. Additionally, tumor lymphocyte infiltration was analyzed by the use of an [89Zr]-labeled anti-PD-1 antibody and measured as 89Zr tumor uptake. Results: Conventional [18F]-FDG-PET scans failed to detect the antitumor activity exerted by anti-PD-1 therapy. However, [89Zr]-anti-PD-1 uptake was substantially higher in mice that responded to PD-1 blockade. The analysis of tumor-infiltrating immune cell populations and interleukins demonstrated an increased anti-tumor effect elicited by activation of effector immune cells in PD-1-responder mice. Interestingly, a positive correlation between [89Zr]-anti-PD-1 uptake and the proportion of tumor-infiltrating lymphocytes (TILs) was found (Cor = 0.8; p = 0.001). Conclusion: Our data may support the clinical implementation of immuno-PET as a promising novel imaging tool to predict and assess the response of PD-1/PD-L1 inhibitors in patients with NSCLC.