Chocarro de Erauso, Luisa
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Chocarro de Erauso
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Luisa
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Ciencias de la Salud
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Publication Open Access Cutting-edge: preclinical and clinical development of the first approved LAG-3 inhibitor(MDPI, 2022) Chocarro de Erauso, Luisa; Bocanegra Gondán, Ana Isabel; Blanco, Ester; Fernández Rubio, Leticia; Arasanz Esteban, Hugo; Echaide Górriz, Míriam; Garnica, Maider; Ramos, Pablo; Piñeiro Hermida, Sergio; Vera García, Ruth; Escors Murugarren, David; Kochan, Grazyna; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako GobernuaImmune checkpoint inhibitors (ICIs) have revolutionized medical practice in oncology since the FDA approval of the first ICI 11 years ago. In light of this, Lymphocyte-Activation Gene 3 (LAG-3) is one of the most important next-generation immune checkpoint molecules, playing a similar role as Programmed cell Death protein 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4). 19 LAG-3 targeting molecules are being evaluated at 108 clinical trials which are demonstrating positive results, including promising bispecific molecules targeting LAG-3 simultaneously with other ICIs. Recently, a new dual anti-PD-1 (Nivolumab) and anti-LAG-3 (Relatimab) treatment developed by Bristol Myers Squibb (Opdualag), was approved by the Food and Drug Administration (FDA) as the first LAG-3 blocking antibody combination for unresectable or metastatic melanoma. This novel immunotherapy combination more than doubled median progression-free survival (PFS) when compared to nivolumab monotherapy (10.1 months versus 4.6 months). Here, we analyze the large clinical trial responsible for this historical approval (RELATIVITY-047), and discuss the preclinical and clinical developments that led to its jump into clinical practice. We will also summarize results achieved by other LAG-3 targeting molecules with promising anti-tumor activities currently under clinical development in phases I, I/II, II, and III. Opdualag will boost the entry of more LAG-3 targeting molecules into clinical practice, supporting the accumulating evidence highlighting the pivotal role of LAG-3 in cancer.Publication Embargo Study of PD-1/LAG-3 signaling in T cells and development of therapeutic strategies to counteract PD-1/LAG-3 mediated resistance to cancer immunotherapy(2025) Chocarro de Erauso, Luisa; Escors Murugarren, David; Kochan, Grazyna; Ciencias de la Salud; Osasun ZientziakA significant number of cancer patients do not benefit from PD-L1/PD-1 blockade immunotherapies. PD-1 and LAG-3 co-upregulation in T-cells is one of the major mechanisms of resistance by establishing a highly dysfunctional state in T-cells. However, how LAG-3 mechanistically triggers its downstream inhibitory signalling remains largely unknown. Likewise, how LAG-3 cooperates with PD-1 to stablish a highly dysfunctional state in T cells in cancer is also unknown. A better understanding of LAG-3 and PD-1/LAG-3 signaling will uncover the reasons behind intrinsic resistance to PD-1 blockade, develop novel treatments and improve current therapies. This PhD thesis comprises the study of PD-1/LAG-3 signaling in T-cells and the development of therapeutic strategies to counteract PD-1/LAG-3-mediated resistance to cancer immunotherapy. The results of this thesis have been organized into three chapters. In chapter 1, PD-1/LAG-3 molecular co-signaling mechanisms were identified in T-cells, uncovering CBLB ubiquitin ligases as potential targets. The combination of CBL-B inhibitors with anti-PD- 1/anti-LAG-3 immunotherapies overcame PD-1/LAG-3-mediated resistance in models of lung cancer refractory to immunotherapies. In chapter 2, the consequences of PD-1/LAG-3 cosignaling over the proteome and phosphoproteome associated to the TCR signalosome were characterized. MYC was identified as an inhibited upstream regulator of PD-1/LAG-3 proteomes and phosphoproteomes in T-cells. In chapter 3, T-cell lines expressing LAG-3 mutants in its signaling domains were engineered and analyzed by quantitative highthroughput differential proteomics and phosphoproteomics. The pathways and molecules regulated by each of LAG-3 domains and their effect on the TCR signalosome both in terms of protein expression and phosphorylation activity were characterized. These results highlighted the critical role of KIEELE and EP domains to endow LAG-3 with inhibitory functions. Overall, the results will help to identify the mechanisms of intrinsic resistance to PD-1 blockade mediated by LAG-3 co-signaling, and uncover novel therapeutic targets to counteract PD- 1/LAG-3-mediated resistance.Publication Open Access PD-1/LAG-3 co-signaling profiling uncovers CBL ubiquitin ligases as key immunotherapy targets(EMBO Press, 2024-07-19) Chocarro de Erauso, Luisa; Blanco, Ester; Fernández-Rubio, Leticia; Garnica, Maider; Zuazo Ibarra, Miren; García Granda, María Jesús; Bocanegra Gondán, Ana Isabel; Echaide Górriz, Míriam; Johnston, Colette; Edwards, Carolyn J.; Legg, James; Pierce, Andrew J.; Arasanz Esteban, Hugo; Fernández Hinojal, Gonzalo; Vera García, Ruth; Ausín, Karina; Santamaría Martínez, Enrique; Fernández Irigoyen, Joaquín; Kochan, Grazyna; Escors Murugarren, David; Ciencias de la Salud; Osasun ZientziakMany cancer patients do not benefit from PD-L1/PD-1 blockade immunotherapies. PD-1 and LAG-3 co-upregulation in T-cells is one of the major mechanisms of resistance by establishing a highly dysfunctional state in T-cells. To identify shared features associated to PD-1/LAG-3 dysfunctionality in human cancers and T-cells, multiomic expression profiles were obtained for all TCGA cancers immune infiltrates. A PD-1/LAG-3 dysfunctional signature was found which regulated immune, metabolic, genetic, and epigenetic pathways, but especially a reinforced negative regulation of the TCR signalosome. These results were validated in T-cell lines with constitutively active PD-1, LAG-3 pathways and their combination. A differential analysis of the proteome of PD-1/LAG-3 T-cells showed a specific enrichment in ubiquitin ligases participating in E3 ubiquitination pathways. PD-1/LAG-3 co-blockade inhibited CBL-B expression, while the use of a bispecific drug in clinical development also repressed C-CBL expression, which reverted T-cell dysfunctionality in lung cancer patients resistant to PD-L1/PD-1 blockade. The combination of CBL-B-specific small molecule inhibitors with anti-PD-1/anti-LAG-3 immunotherapies demonstrated notable therapeutic efficacy in models of lung cancer refractory to immunotherapies, overcoming PD-1/LAG-3 mediated resistance. © The Author(s) 2024.