JULIANA MACHADO RUGOLO
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conferenceObject Immune Profiling Data and Mutational Status Improves Prediction of Risk of Death in Non-Small Cell Lung Carcinoma(2019) PARRA, E.; JANG, M.; MACHADO-RUGOLO, J.; FARHAT, C.; NAGAI, M.; TAKAGAKI, T.; TERRA, R.; FABRO, A.; CAPELOZZI, V.- The Immunological Landscape of M1 and M2 Macrophages and Their Spatial Distribution in Patients with Malignant Pleural Mesothelioma(2023) LABERIANO-FERNANDEZ, Caddie; BALDAVIRA, Camila Machado; MACHADO-RUGOLO, Juliana; TAMEGNON, Auriole; PANDURENGAN, Renganayaki Krishna; AB'SABER, Alexandre Muxfeldt; BALANCIN, Marcelo Luiz; TAKAGAKI, Teresa Yae; NAGAI, Maria Aparecida; CAPELOZZI, Vera Luiza; PARRA, Edwin RogerSimple Summary Identifying biomarkers to guide immunotherapy regimens remains an unmet clinical need in malignant pleural mesothelioma. A potential source of such markers is tumor-associated macrophages (TAMs), which contribute to the immunosuppressive microenvironment of mesothelioma. By examining distinct subsets of pleural macrophages to identify their gene signatures and protein expression, we found that TAMs preferentially contribute to M2a and M2b phenotypes, and M2a, M2b, and M2c more specifically contributed to immune tolerance. CD206, ARG1, CD274, CD163, and MRP8-14 are potential therapeutic targets in this disease.Abstract Background: Several tumor-associated macrophages (TAMs) have shown promise as prognosticators in cancer. Our aim was to validate the importance of TAMs in malignant pleural mesothelioma (MPM) using a two-stage design. Methods: We explored The Cancer Genome Atlas (TCGA-MESO) to select immune-relevant macrophage genes in MPM, including M1/M2 markers, as a discovery cohort. This computational cohort was used to create a multiplex immunofluorescence panel. Moreover, a cohort of 68 samples of MPM in paraffin blocks was used to validate the macrophage phenotypes and the co-localization and spatial distribution of these immune cells within the TME and the stromal or tumor compartments. Results: The discovery cohort revealed six immune-relevant macrophage genes (CD68, CD86, CD163, CD206, ARG1, CD274), and complementary genes were differentially expressed by M1 and M2 phenotypes with distinct roles in the tumor microenvironment and were associated with the prognosis. In addition, immune-suppressed MPMs with increased enrichment of CD68, CD86, and CD163 genes and high densities of M2 macrophages expressing CD163 and CD206 proteins were associated with worse overall survival (OS). Interestingly, below-median distances from malignant cells to specific M2a and M2c macrophages were associated with worse OS, suggesting an M2 macrophage-driven suppressive component in these tumors. Conclusions: The interactions between TAMs in situ and, particularly, CD206+ macrophages are highly relevant to patient outcomes. High-resolution technology is important for identifying the roles of macrophage populations in tissue specimens and identifying potential therapeutic candidates in MPM.
- Variants in Epithelial-Mesenchymal Transition and Immune Checkpoint Genes Are Associated With Immune Cell Profiles and Predict Survival in Non-Small Cell Lung Cancer(2020) PARRA, Edwin Roger; JIANG, Mei; MACHADO-RUGOLO, Juliana; YAEGASHI, Lygia Bertalha; PRIETO, Tabatha; FARHAT, Cecilia; SA, Vanessa Karen de; NAGAI, Maria Aparecida; LIMA, Vladmir Claudio Cordeiro de; TAKAGAKI, Tereza; TERRA, Ricardo; FABRO, Alexandre Todorovic; CAPELOZZI, Vera LuizaContext.-Identification of gene mutations that are indicative of epithelial-mesenchymal transition and a noninflammatory immune phenotype may be important for predicting response to immune checkpoint inhibitors. Objective.-To evaluate the utility of multiplex immunofluorescence for immune profiling and to determine the relationships among tumor immune checkpoint and epithelial-mesenchymal transition genomic profiles and the clinical outcomes of patients with nonmetastatic non-small cell lung cancer. Design.-Tissue microarrays containing 164 primary tumor specimens from patients with stages I to IIIA non-small cell lung carcinoma were examined by multiplex immunofluorescence and image analysis to determine the expression of programmed death ligand-1 (PD-L1) on malignant cells, CD68; macrophages, and cells expressing the immune markers CD3, CD8, CD57, CD45RO, FOXP3, PD-1, and CD20. Immune phenotype data were tested for correlations with clinicopathologic characteristics, somatic and germline genetic variants, and outcome. Results.-A high percentage of PD-L1(+) malignant cells was associated with clinicopathologic characteristics, and high density of CD3+PD-1(+) T cells was associated with metastasis, suggesting that these phenotypes may be clinically useful to identify patients who will likely benefit from immunotherapy. We also found that ZEB2 mutations were a proxy for immunologic ignorance and immune tolerance microenvironments and may predict response to checkpoint inhibitors. A multivariate Cox regression model predicted a lower risk of death for patients with a high density of CD3(+)CD45RO(+) memory T cells, carriers of allele G of CTLA4 variant rs231775, and those whose tumors do not have ZEB2 mutations. Conclusions.-Genetic variants in epithelial mesenchymal transition and immune checkpoint genes are associated with immune cell profiles and may predict patient outcomes and response to immune checkpoint blockade.
- Association of Functional Polymorphism in CTLA-4 Gene with Survival in Non-Small Cell Lung Cancer: A Brazilian Study(2018) MACHADO-RUGOLO, J.; FABRO, A.; CUENTAS, E.; SA, V. De; RAINHO, C.; NAGAI, M.; CAPELOZZI, V.; BALANCIN, M.
- Relevance of PD-L1 Non-Coding Polymorphisms on the Prognosis of a Genetically Admixed NSCLC Cohort(2021) MACHADO-RUGOLO, Juliana; PRIETO, Tabatha Gutierrez; FABRO, Alexandre Todorovic; CUENTAS, Edwin Roger Parra; SA, Vanessa Karen; BALDAVIRA, Camila Machado; RAINHO, Claudia Aparecida; CASTELLI, Erick C.; FARHAT, Cecilia; TAKAGAKI, Teresa Yae; NAGAI, Maria Aparecida; CAPELOZZI, Vera LuizaPurpose: Although non-small cell lung cancer (NSCLC) remains a deadly disease, new predictive biomarkers have emerged to assist in managing the disease, of which one of the most promising is the programmed death-ligand 1 (PD-L1). Each, PD-L1 variant seem to modulate the function of immune checkpoints differently and affect response to adjuvant treatment and outcome in NSCLC patients. We thus investigated the influence of these PD-L1 genetic variations in genetically admixed NSCLC tissue samples, and correlated these values with clinicopathological characteristics, including prognosis. Materials and Methods: We evaluated PD-L1 non-coding genetic variants and protein expression in lung adenocarcinomas (ADC), squamous cell carcinomas (SqCC), and large cell carcinomas (LCC) in silico. Microarray paraffin blocks from 70 samples of ADC (N=33), SqCC (N=24), and LCC (N=13) were used to create PD-L1 multiplex immunofluorescence assays with a Cell Signaling E1L3N clone. Fifteen polymorphisms of the PD-L1 gene were investigated by targeted sequencing and evaluated in silico using dedicated tools. Results: Although PD-L1 polymorphisms seemed not to interfere with protein expression, PD-L1 expression varied among different histological subtypes, as did clinical outcomes, with the rs4742098A>G, rs4143815G>C, and rs7041009G>A variants being associated with relapse (P=0.01, P=0.05, P=0.02, respectively). The rs7041009 GG genotype showed a significant correlation with younger and alive patients compared to carriers of the A allele (P=0.02 and P<0.01, respectively). The Cox regression model showed that the rs7041009 GG genotype may influence OS (P<0.01) as a co-dependent factor associated with radiotherapy and recurrence in NSCLC patients. Furthermore, the Kaplan-Meier survival curves showed that rs7041009 and rs4742098 might impact PPS in relapsed patients. In silico approaches identified the variants as benign. Conclusion: PD-L1 non-coding variants play an important role in modulating immune checkpoint function and may be explored as immunotherapy biomarkers. We highlight the rs7041009 variant, which impacts OS and PPS in NSCLC patients.