Open Access
Metabolic dyshomeostasis induced by SARS-CoV-2 structural proteins reveals immunological insights into viral olfactory interactions
(Frontiers Media, 2022) Lachén Montes, Mercedes; Mendizuri, Naroa; Ausín, Karina; Echaide Górriz, Míriam; Blanco, Ester; Chocarro de Erauso, Luisa; Toro, María de; Escors Murugarren, David; Fernández Irigoyen, Joaquín; Kochan, Grazyna; Santamaría Martínez, Enrique; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua
One of the most common symptoms in COVID-19 is a sudden loss of smell. SARS-CoV-2 has been detected in the olfactory bulb (OB) from animal models and sporadically in COVID-19 patients. To decipher the specific role over the SARS-CoV-2 proteome at olfactory level, we characterized the in-depth molecular imbalance induced by the expression of GFP-tagged SARS-CoV-2 structural proteins (M, N, E, S) on mouse OB cells. Transcriptomic and proteomic trajectories uncovered a widespread metabolic remodeling commonly converging in extracellular matrix organization, lipid metabolism and signaling by receptor tyrosine kinases. The molecular singularities and specific interactome expression modules were also characterized for each viral structural factor. The intracellular molecular imbalance induced by each SARS-CoV-2 structural protein was accompanied by differential activation dynamics in survival and immunological routes in parallel with a differentiated secretion profile of chemokines in OB cells. Machine learning through a proteotranscriptomic data integration uncovered TGF-beta signaling as a confluent activation node by the SARS-CoV-2 structural proteome. Taken together, these data provide important avenues for understanding the multifunctional immunomodulatory properties of SARS-CoV-2 M, N, S and E proteins beyond their intrinsic role in virion formation, deciphering mechanistic clues to the olfactory inflammation observed in COVID-19 patients.
Open Access
A proteomic atlas of lineage and cancer-polarized expression modules in myeloid cells modeling immunosuppressive tumor-infiltrating subsets
(MDPI, 2021) Blanco, Ester; Ibañez Vea, María; Hernández, Carlos; Drici, Lylia; Martínez de Morentin Iribarren, Xabier; Gato Cañas, María; Ausín, Karina; Bocanegra Gondán, Ana Isabel; Zuazo Ibarra, Miren; Chocarro de Erauso, Luisa; Arasanz Esteban, Hugo; Fernández Hinojal, Gonzalo; Fernández Irigoyen, Joaquín; Smerdou, Cristian; Garnica, Maider; Echaide Górriz, Míriam; Fernández Rubio, Leticia; Morente Sancho, Pilar; Ramos-Castellanos, Pablo; Llopiz, Diana; Santamaría Martínez, Enrique; Larsen, Martin R.; Escors Murugarren, David; Kochan, Grazyna; Osasun Zientziak; Institute for Multidisciplinary Research in Applied Biology - IMAB; Ciencias de la Salud; Gobierno de Navarra / Nafarroako Gobernua
Monocytic and granulocytic myeloid-derived suppressor cells together with tumor-infiltrating macrophages constitute the main tumor-infiltrating immunosuppressive myeloid populations. Due to the phenotypic resemblance to conventional myeloid cells, their identification and purification from within the tumors is technically difficult and makes their study a challenge. We differentiated myeloid cells modeling the three main tumor-infiltrating types together with uncommitted macrophages, using ex vivo differentiation methods resembling the tumor microenvironment. The phenotype and proteome of these cells was compared to identify linage-dependent relationships and cancer-specific interactome expression modules. The relationships between monocytic MDSCs and TAMs, monocytic MDSCs and granulocytic MDSCs, and hierarchical relationships of expression networks and transcription factors due to lineage and cancer polarization were mapped. Highly purified immunosuppressive myeloid cell populations that model tumor-infiltrating counterparts were systematically analyzed by quantitative proteomics. Full functional interactome maps have been generated to characterize at high resolution the relationships between the three main myeloid tumor-infiltrating cell types. Our data highlights the biological processes related to each cell type, and uncover novel shared and differential molecular targets. Moreover, the high numbers and fidelity of ex vivo-generated subsets to their natu-ral tumor-shaped counterparts enable their use for validation of new treatments in high-throughput experiments.
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 Zientziak
Many 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.

Santamaría Martínez, Enrique

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