Morilla Ruiz, Idoia
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Morilla Ruiz
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Idoia
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Ciencias de la Salud
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Publication Open Access PD-L1 expression in systemic immune cell populations as a potential predictive biomarker of responses to PD-L1/PD-1 blockade therapy in lung cancer(MDPI, 2019) Bocanegra Gondán, Ana Isabel; Fernández Hinojal, Gonzalo; Zuazo Ibarra, Miren; Arasanz Esteban, Hugo; García Granda, María Jesús; Hernández, Carlos; Ibañez Vea, María; Hernandez Marin, Berta; Martínez Aguillo, Maite; Lecumberri, María José; Fernández de Lascoiti, Ángela; Teijeira, Lucía; Morilla Ruiz, Idoia; Vera García, Ruth; Escors Murugarren, David; Kochan, Grazyna; Ciencias de la Salud; Osasun Zientziak; Universidad Pública de Navarra / Nafarroako Unibertsitate PublikoaPD-L1 tumor expression is a widely used biomarker for patient stratification in PD-L1/PD-1 blockade anticancer therapies, particularly for lung cancer. However, the reliability of this marker is still under debate. Moreover, PD-L1 is widely expressed by many immune cell types, and little is known on the relevance of systemic PD-L1+ cells for responses to immune checkpoint blockade. We present two clinical cases of patients with non-small cell lung cancer (NSCLC) and PD-L1-negative tumors treated with atezolizumab that showed either objective responses or progression. These patients showed major differences in the distribution of PD-L1 expression within systemic immune cells. Based on these results, an exploratory study was carried out with 32 cases of NSCLC patients undergoing PD-L1/PD-1 blockade therapies, to compare PD-L1 expression profiles and their relationships with clinical outcomes. Significant differences in the percentage of PD-L1+ CD11b+ myeloid cell populations were found between objective responders and non-responders. Patients with percentages of PD-L1+ CD11b+ cells above 30% before the start of immunotherapy showed response rates of 50%, and 70% when combined with memory CD4 T cell profiling. These findings indicate that quantification of systemic PD-L1+ myeloid cell subsets could provide a simple biomarker for patient stratification, even if biopsies are scored as PD-L1 nullPublication Open Access Early detection of hyperprogressive disease in non-small cell lung cancer by monitoring of systemic T cell dynamics(MDPI, 2020) Arasanz Esteban, Hugo; Zuazo Ibarra, Miren; Bocanegra Gondán, Ana Isabel; Gato Cañas, María; Martínez Aguillo, Maite; Morilla Ruiz, Idoia; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua; Universidad Pública de Navarra / Nafarroako Unibertsitate PublikoaHyperprogressive disease (HPD) is an adverse outcome of immunotherapy consisting of an acceleration of tumor growth associated with prompt clinical deterioration. The definitions based on radiological evaluation present important technical limitations. No biomarkers have been identified yet. In this study, 70 metastatic NSCLC patients treated with anti-PD-1/PD-L1 immunotherapy after progression to platinum-based therapy were prospectively studied. Samples from peripheral blood were obtained before the first (baseline) and second cycles of treatment. Peripheral blood mononuclear cells (PBMCs) were isolated and differentiation stages of CD4 lymphocytes quantified by flow cytometry and correlated with HPD as identified with radiological criteria. A strong expansion of highly differentiated CD28− CD4 T lymphocytes (CD4 THD) between the first and second cycle of therapy was observed in HPD patients. After normalizing, the proportion of posttreatment/pretreatment CD4 THD was significantly higher in HPD when compared with the rest of patients (median 1.525 vs. 0.990; p = 0.0007), and also when stratifying by HPD, non-HPD progressors, and responders (1.525, 1.000 and 0.9700 respectively; p = 0.0025). A cutoff value of 1.3 identified HPD with 82% specificity and 70% sensitivity. An increase of CD28− CD4 T lymphocytes ≥ 1.3 (CD4 THD burst) was significantly associated with HPD (p = 0.008). The tumor growth ratio (TGR) was significantly higher in patients with expansion of CD4 THD burst compared to the rest of patients (median 2.67 vs. 0.86, p = 0.0049), and also when considering only progressors (median 2.67 vs. 1.03, p = 0.0126). A strong expansion of CD28− CD4 lymphocytes in peripheral blood within the first cycle of therapy is an early differential feature of HPD in NSCLC treated with immune-checkpoint inhibitors. The monitoring of T cell dynamics allows the early detection of this adverse outcome in clinical practice and complements radiological evaluation.