Genetic Polymorphisms of the TGFB1 Signal Peptide and Promoter Region: Role in Wilms Tumor Susceptibility?

The aim of the present study was to investigate the rs1800468 (G-800A), rs1800469 (C-509T), rs1800470 (C29T), and rs1800471 (G74C) TGFB1 genetic polymorphisms and their haplotype structures in patients with Wilms Tumor (WT) and neoplasia-free controls. The genomic DNA was extracted from 35 WT patients and 160 neoplasia-free children, and the TGFB1 polymorphisms were genotyped by polymerase chain reaction, followed by restriction fragment length polymorphism. The haplotype structures were inferred, and permutation and logistic regression tests were performed to check for differences in haplotype distribution between the control and WT individuals. Positive associations were found in the recessive model for rs1800469 T allele (OR: 8.417; 95% CI: 3.177 to 22.297; P < 0.001) and for the rs1800470 C allele (OR: 3.000; 95% CI: 1.296 to 6.944; P = 0.01). Haplotype analysis revealed a significant negative association between GCTG and WT (OR: 0.236, 95% CI: 0.105 to 0.534; P = 0.0002); by contrast, the GTTG haplotype was associated with increased risk for WT (OR: 12.0; 95% CI: 4.202 to 34.270; P < 0.001). Furthermore, rs1800469 was negatively correlated with tumor size and a trend toward a positive correlation for capsular invasion was observed in the dominant model (Tau-b: −0.43, P = 0.02 and tau-b: 0.5, P = 0.06, respectively). This is the first study with rs1800468, rs1800469, rs1800470, and rs1800471 TGFB1 polymorphisms in WT, and our results suggest that the TGFB1 promoter and signal peptide region polymorphisms may be associated with WT susceptibility and clinical presentation

Antiviral responses in cancer: boosting antitumor immunity through activation of interferon pathway in the tumor microenvironment

This work was supported by funds from the São Paulo Research Foundation (FAPESP) to GV (fellowship 2020/10299-7) and TM (grant 2018/14034-8), by grants from the National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation (INCITO) funded by FAPESP (grant 2014/50943- 1), and the National Council for Scientific and Technological Development (CNPq, grant 465682/2014-6).International Research Center, A.C. Camargo Cancer Center. Translational Immuno-Oncology Group. São Paulo, SP, BrazilInternational Research Center, A.C. Camargo Cancer Center. Translational Immuno-Oncology Group. São Paulo, SP, Brazil / Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Laboratório de Citogenômica e Mutagênese Ambiental. Ananindeua, PA, BrasilDepartment of Clinical Oncology, A.C. Camargo Cancer Center. São Paulo, SP, BrazilInternational Research Center, A.C. Camargo Cancer Center. Translational Immuno-Oncology Group. São Paulo, SP, Brazil / National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation. São Paulo, SP, BrazilIn recent years, it became apparent that cancers either associated with viral infections or aberrantly expressing endogenous retroviral elements (EREs) are more immunogenic, exhibiting an intense intra-tumor immune cell infiltration characterized by a robust cytolytic apparatus. On the other hand, epigenetic regulation of EREs is crucial to maintain steady-state conditions and cell homeostasis. In line with this, epigenetic disruptions within steady-state cells can lead to cancer development and trigger the release of EREs into the cytoplasmic compartment. As such, detection of viral molecules by intracellular innate immune sensors leads to the production of type I and type III interferons that act to induce an antiviral state, thus restraining viral replication. This knowledge has recently gained momentum due to the possibility of triggering intratumoral activation of interferon responses, which could be used as an adjuvant to elicit strong anti-tumor immune responses that ultimately lead to a cascade of cytokine production. Accordingly, several therapeutic approaches are currently being tested using this rationale to improve responses to cancer immunotherapies. In this review, we discuss the immune mechanisms operating in viral infections, show evidence that exogenous viruses and endogenous retroviruses in cancer may enhance tumor immunogenicity, dissect the epigenetic control of EREs, and point to interferon pathway activation in the tumor milieu as a promising molecular predictive marker and immunotherapy target. Finally, we briefly discuss current strategies to modulate these responses within tumor tissues, including the clinical use of innate immune receptor agonists and DNA demethylating agents

Comprehensive analysis of epigenetics regulation, prognostic and the correlation with immune infiltrates of GPX7 in adult gliomas

Instituto Evandro Chagas (Brazil) and Pro-Reitoria de Pesquisa e Pos-GraduacAo (PROPESP/UFPA, Brazil)Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Laboratório de Citogenômica e Mutagênese Ambiental. Ananindeua, PA, BrasilA.C. Camargo Cancer Center. International Research Center. Translational Immuno‑Oncology Group. São Paulo, SP, BrazilA.C. Camargo Cancer Center. International Research Center. Translational Immuno‑Oncology Group. São Paulo, SP, Brazil / National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation. São Paulo, SP, Brazil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Laboratório de Citogenômica e Mutagênese Ambiental. Ananindeua, PA, Brasil / Federal University of Pará. Faculty of Natural Sciences. Institute of Exact and Natural Sciences. Belém, PA, BrazilGliomas are the most commonly occurring malignant brain tumor characterized by an immunosuppressive microenvironment accompanied by profound epigenetic changes, thus influencing the prognosis. Glutathione peroxidase 7 (GPX7) is essential for regulating reactive oxygen species homeostasis under oxidative stress. However, little is known about the function of GPX7 in gliomas. In this study, we hypothesized that GPX7 methylation status could influence biological functions and local immune responses that ultimately impact prognosis in adult gliomas. We conducted an integrated bioinformatics analysis mining GPX7 DNA methylation status, transcriptional and survival data of glioma patients. We discovered that GPX7 was remarkably increased in glioma tissues and cell lines, and was associated with poor prognosis. This upregulation was significantly linked to clinicopathological and molecular features, besides being expressed in a cell cycle-dependent manner. Our results consistently demonstrated that upregulation of GPX7 is tightly modulated by epigenetic processes, which also impacted the overall survival of patients with low-grade gliomas (LGG). Based on the analysis of biological functions, we found that GPX7 might be involved in immune mechanisms involving both innate and adaptive immunity, type I interferon production and regulation of synaptic transmission in LGG, whereas in GBM, it is mainly related to metabolic regulation of mitochondrial dynamics. We also found that GPX7 strongly correlates with immune cell infiltration and diverse immune cell markers, suggesting its role in tumor-specific immune response and in regulating the migration of immune cell types to the tumor microenvironment. Combining these multiple data, we provided the first evidence regarding the epigenetic-mediated regulatory mechanisms underlying GPX7 activation in gliomas. Furthermore, our study brings key insights into the significant effect of GPX7 in modulating both immune molecules and in immune cell infiltration in the microenvironment of gliomas, which might impact the patient outcome, opening up future opportunities to regulate the local immune response

FOXP3 Allelic Variants and Haplotype Structures Are Associated with Aggressive Breast Cancer Subtypes

FOXP3 genetic polymorphisms have been associated with cancer development and prognosis. In this context, the present study aimed to evaluate the g.10403A>G (rs2232365) polymorphisms and g.8048A>C (rs3761548), in aggressive breast cancer (BC) subtypes, including, Luminal B HER2+ (LB), HER2-enriched (HER2+), and triple-negative (TN). Polymerase chain reaction followed by enzymatic restriction was performed to genotyping 117 BC samples and 300 controls. A significant association of AA genotype (g.10403A>G) in relation to BC susceptibility (OR = 1.93; 95% CI = 1.01–3.66; p=0.046) was observed. The GG (g.10403A>G) genotype was correlated with higher proliferation index (Ki-67) in HER2+ subtype (τ = 0.47; p=0.019) and advanced TNM staging in TN (τ = 0.23; p=0.032). A correlation of AA genotype (g.8048A>C) with higher Ki-67 (τ = −0.47; p=0.018) and lower histological grade (τ = 0.39; p=0.026) in HER2+ was also found. GA haplotype was correlated with lower histological grade (τ = −0.15; p=0.009) and higher Ki-67 (τ = 0.43; p=0.036) in HER2+ and advanced staging in TN (τ = 0.29; p=0.044). On the other hand, AC haplotype was correlated with lower Ki-67 (τ = −0.54; p=0.005) and staging (τ = −0.29; p=0.027) in HER2+ and TN respectively. Results showed that FOXP3 influence regarding clinical outcome depends greatly on the BC subtype and indicated this transcription factor as a promising marker in aggressive BC subtypes

Involvement of transforming growth factor beta-1 (TGFβ1) cytokine and FOXP3 transcription factor genetic polymorphisms in hematological malignancies

Hematological malignancies (HM) are a group of neoplastic diseases that arise from hematologic cell lineages. Transforming growth factor beta 1 (TGFβ1) is shown to negatively regulate normal and malignant hematopoiesis and, in immunological context, to promote T cell exhaustion and generation of regulatory T cells, which are shown to be deleterious in cancer, by the induction of transcription factor FOXP3 expression. The present study aimed to evaluate TGFB1 exon-1 rs1800470 and FOXP3 intron-1 rs2232365 polymorphisms in relation to HM susceptibility. DNA was extracted from blood samples of 43 HM patients and 142 neoplasia-free individuals and polymorphisms were analyzed by allelic-specific PCR. Association analysis was assessed by the Odds Ratio (OR) with significance level of 5%. Regarding FOXP3 polymorphism, no significant differences were observed in genotype or allele distribution among the patients and controls. However, there was a positive association between TGFB1 TT genotype and HM susceptibility (OR = 4.07; CI95% = 1.94 - 8.52). In the combined analysis, a positive association was also observed for TGFB1 TT and FOXP3 GG genotypes (OR = 4.00; CI95% = 1.54 - 10.41) in relation to HM susceptibility. Our results indicated promising new markers to be further investigated in hematological malignancies

B Cell orchestration of anti-tumor immune responses: a matter of cell localization and communication

This work was supported by funds from the São Paulo Research Foundation (FAPESP) to GK (fellowship 2019/25129- 2) and TM (grant 2018/14034-8), by the Coordination for the Improvement of Higher Education Personnel (CAPES) fellowship to AC, by grants from the National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation (INCITO) funded by FAPESP (grant 2014/50943-1), and the National Council for Scientific and Technological Development (CNPq, grant 465682/2014-6).A.C. Camargo Cancer Center. International Research Center. Translational Immuno-oncology Group. São Paulo, SP, Brazil.A.C. Camargo Cancer Center. International Research Center. Translational Immuno-oncology Group. São Paulo, SP, Brazil / Londrina State University. Department of Pathological Sciences. Londrina, PR, Brazil.A.C. Camargo Cancer Center. International Research Center. Translational Immuno-oncology Group. São Paulo, SP, Brazil / Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Laboratório de Cultura de Tecidos e Citogenética. Ananindeua, PA, Brasil.A.C. Camargo Cancer Center. International Research Center. Translational Immuno-oncology Group. São Paulo, SP, Brazil.Instituto do Câncer do Estado de São Paulo. São Paulo, SP, Brazil / D’Or São Paulo. Rede D’or.Oncologia. São Paulo, SP, Brazil.A.C. Camargo Cancer Center. International Research Center. Translational Immuno-oncology Group. São Paulo, SP, Brazil / National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation. São Paulo, SP, Brazil.The immune system plays a crucial role in cancer development either by fostering tumor growth or destroying tumor cells, which has open new avenues for cancer immunotherapy. It was only over the last decade that the role of B cells in controlling anti-tumor immune responses in the tumor milieu has begun to be appreciated. B and plasma cells can exert anti-tumor effects through antibody-dependent cell cytotoxicity (ADCC) and activation of the complement cascade, even though their effector functions extend beyond the classical humoral immunity. In tumor tissues, B cells can be found in lymphoid aggregates, known as tertiary lymphoid structures (TLSs), well-organized non-encapsulated structures composed of immune and stromal cells. These structures reflect a process of lymphoid neogenesis occurring in peripheral tissues upon long-lasting exposure to inflammatory signals. The TLS provides an area of intense B cell antigen presentation that can lead to optimal T cell activation and effector functions, as well as the generation of effector B cells, which can be further differentiated in either antibody-secreting plasma cells or memory B cells. Of clinical interest, the crosstalk between B cells and antigen-experienced and exhausted CD8(+) T cells within mature TLS was recently associated with improved response to immune checkpoint blockade (ICB) in melanoma, sarcoma and lung cancer. Otherwise, B cells sparsely distributed in the tumor microenvironment or organized in immature TLSs were found to exert immune-regulatory functions, inhibiting anti-tumor immunity through the secretion of anti-inflammatory cytokines. Such phenotype might arise when B cells interact with malignant cells rather than T and dendritic cells. Differences in the spatial distribution likely underlie discrepancies between the role of B cells inferred from human samples or mouse models. Many fast-growing orthotopic tumors develop a malignant cell-rich bulk with reduced stroma and are devoid of TLSs, which highlights the importance of carefully selecting pre-clinical models. In summary, strategies that promote TLS formation in close proximity to tumor cells are likely to favor immunotherapy responses. Here, the cellular and molecular programs coordinating B cell development, activation and organization within TLSs will be reviewed, focusing on their translational relevance to cancer immunotherapy

Absence of Association between CCR5

Acute lymphoblastic leukemia (ALL) is a malignant disorder that originates from one single hematopoietic precursor committed to B- or T-cell lineage. Ordinarily, these cells express CCR5 chemokine receptor, which directs the immune response to a cellular pattern and is involved in cancer pathobiology. The genetic rs333 polymorphism of CCR5 (Δ32), results in a diminished receptor expression, thus leading to impaired cell trafficking. The objective of the present study was to investigate the effect of CCR5 chemokine receptor rs333 polymorphism in the pathogenesis of ALL. The genotype distribution was studied in 79 patients and compared with 80 control subjects, in a childhood population of Southern Brazil. Genotyping was performed using DNA samples amplified by polymerase chain reaction with sequence-specific primers (PCR-SSP). The homozygous (Δ32/Δ32) deletion was not observed in any subject involved in the study. Heterozygous genotype was not associated with ALL risk (OR 0.7%; 95% CI 0.21–2.32; P>0.05), nor recurrence status of ALL (OR 0.86; 95% CI 0.13–5.48; P>0.05). This work demonstrated, for the first time, no significant differences in the frequency of the CCR5/Δ32 genotype between ALL and control groups, indicating no effect of this genetic variant on the ALL susceptibility and recurrence risk