Immunobiology Seminar Fordham

Talita Aguiar, Ph.DImmunobiology Seminar - Fordham College at Lincoln Center Campus (LL816) | Thursday, March 14th 2024.

Intersecting Frontiers: Uniting Genetic,Epigenetic and translational Immunology

START

Who I am?

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

Postdoctoral Research Scientist ny

PHD INTERSHIP TEXAS CHILDREN`S HOSPITAL

Ph.D in molecular oncology - BRAZIL

MBA in Health Management, Innovation, and Services

Biomedical science

Talita Aguiar, Ph.D - Immunobiology Seminar

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Talita Aguiar, Ph.D - Immunobiology Seminar

cancer

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01

Cancer is a genetic disease, influenced by other million factors...

The Emperor of All Maladies

“Cancer begins and ends with people. In the midst of scientific abstraction, it is sometimes possible to forget this one basic fact.…”

Urbanization and the "modern lifestyle"

WHY SHOULD WE STUDY CANCER?

Talita Aguiar, Ph.D - Immunobiology Seminar

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WHY SHOULD WE STUDY CANCER?

Talita Aguiar, Ph.D - Immunobiology Seminar

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WHY SHOULD WE STUDY CANCER?

Talita Aguiar, Ph.D - Immunobiology Seminar

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Understand the disparities: Cancer's rising prominence as a leading cause of death partly reflects marked declines in mortality rates of stroke and coronary heart disease, relative to cancer, in many countries

WHY SHOULD WE STUDY CANCER?

Talita Aguiar, Ph.D - Immunobiology Seminar

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Talita Aguiar, Ph.D - Immunobiology Seminar

PEDIATRIC TUMORS

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02

An Early Start On Tackling Childhood Cancers. Nature; V. 543, P. 590. 2017.

1- Do statistics tell the whole story?2- Does childhood cancer have borders?3- Is childhood cancer curable?4- Will children live longer, but will they live with quality?

CHILDHOOD CANCER: A PUBLIC HEALTH PROBLEM?

Talita Aguiar, Ph.D - Immunobiology Seminar

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Source: NCCR*Explorer: An interactive website for NCCR cancer statistics. National Cancer Institute. Accessed at nccrexplorer.ccdi.cancer.govYears 2015-2019, By Cancer Site, Both Sexes, All Races, Ages <20.

Prevalence of pediatric cancers (0-19 years)

Talita Aguiar, Ph.D - Immunobiology Seminar

PREVALENCE

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Source: NCCR*Explorer: An interactive website for NCCR cancer statistics. National Cancer Institute. Accessed at nccrexplorer.ccdi.cancer.gov

1430 died by the disease

Talita Aguiar, Ph.D - Immunobiology Seminar

INCIDENCE, MORTALITY AND MORE

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83.5% of families with a child with cancer will experience some level of financial hardship

Talita Aguiar, Ph.D - Immunobiology Seminar

"Beyond, pero no much" biological science

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75% of families with a child with cancer will have at least one parent who needs to cut back on work or stop working all together

Talita Aguiar, Ph.D - Immunobiology Seminar

"Beyond, pero no much" biological science

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67.3% of families with a child with cancer have health insurance through the parent`s employer. This is either canceled or changed if the parent has to quit their job

Talita Aguiar, Ph.D - Immunobiology Seminar

"Beyond, pero no much" biological science

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2 out 3 childhood cancer survivors will develop at least one chronic health condition due to toxic treatment.

Talita Aguiar, Ph.D - Immunobiology Seminar

"Beyond, pero no much" biological science

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Most standard childhood cancer treatments are decades old

Talita Aguiar, Ph.D - Immunobiology Seminar

"Beyond, pero no much" biological science

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Talita Aguiar, Ph.D - Immunobiology Seminar

THE ATTENTION FOR RARE DISEASES

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Talita Aguiar, Ph.D - Immunobiology Seminar

THE ATTENTION FOR RARE DISEASES

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Talita Aguiar, Ph.D - Immunobiology Seminar

MULTIDISCIPLINARITY

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https://www.cancer.gov/types/childhood-cancers

Early signs of pediatric cancer can be subtle and confuse the diagnosis with other common childhood illnesses

Talita Aguiar, Ph.D - Immunobiology Seminar

SYMPTONS

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TOMLINSON et al, 2012; AGUIAR et al. 2017; JOHNSON et al. 2017

10-15% of pediatric tumors would be caused by inherited germline mutations or new mutations (de novo, not present in the parents) in cancer predisposition genes, such as mutations in the RB1 or TP53 gene;

90% - are multifactorial, which is the combination of the action of somatic mutations and environmental factors

Talita Aguiar, Ph.D - Immunobiology Seminar

RISK FACTORS

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Hanahan, Douglas. “Hallmarks of Cancer: New Dimensions.” Cancer discovery 12 1 (2022): 31-46 .

Hallmarks of cancer

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WHY CHILDREN ALSO HAVE CANCER?

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Somatic mutations

GRÖBNER et al. 2018

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WHY CHILDREN ALSO HAVE CANCER?

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Talita Aguiar, Ph.D - Immunobiology Seminar

PEDIATRIC MATCH

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GENOMIC ALTERATIONS OF HEPATOBLASTOMA

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03

ZORN et al. 2008

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EMBRYONAL TUMOR OF LIVER

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• Primary hepatic neoplasms are rare in children: ~ 2.9% of all pediatric cancers

• HB: liver tumor more frequent in children: 1% of all cancers in this age group

• SEER (between 2014-2018): 2.9 HB in one million children and adolescents <20 yrs old

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HEPATOBLASTOMA (HB)

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GRÖBNER et al. 2018

Talita Aguiar, Ph.D - Immunobiology Seminar

HB has the lower number of somatic mutations

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The identification of the molecular pathways involved in HB development can expand the understanding of the connections between disruption of normal differentiation and pediatric liver cancer.

Talita Aguiar, Ph.D - Immunobiology Seminar

HB: SOMATIC MUTATIONS

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Talita Aguiar, Ph.D - Immunobiology Seminar

HB: SOMATIC MUTATIONS

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• Rodrigues, T. C. et al. Future Oncol. (2014).
• Maschietto, M. et al. Oncotarget (2017).
• Aguiar, T. F. M. et al. Appl. Cancer Res. (2017).
• Aguiar TFM. et al. Pediatric blood & cancer (2018).
• Rivas, M. P. et al. Front. Genet. (2019).
• Rivas M., Ferreira S., Aguiar T. Genética na Escola. (2019).
• Aguiar T. et al., Front Oncol. (2020).
• Aguiar T. and Teixeira A. et al. Authorea Preprints, 7 (2020).
• Rivas M., Aguiar T., et al. Tumour Biol. (2020).
• Rivas M., Aguiar T. et al. Clinics and Research in Hepatology and Gastroenterology (2021).

• JS Barros, TFM Aguiar, SS Costa, MP Rivas et al. Frontiers in Oncology (2021).
• T Aguiar, A Teixeira, J Sobral de Barros et al. Frontiers in Genetics (2022).
• L Tasic, N Avramović, M Jadranin et al. Biomedicines (2022).
• GD Dangoni, ACB Teixeira, TF Aguiar et al. Pediatric Blood and Cancer (2023).

• TFM Aguiar, MP Rivas et al. Biochemical Genetics (in press 2024).

Talita Aguiar, Ph.D - Immunobiology Seminar

HUMAN GENETICS LAB (IB/USP)

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Talita Aguiar, Ph.D - Immunobiology Seminar

PATIENTS

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AGUIAR et al. 2020

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SOMATIC MUTATIONS

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EXOME SEQUENCING

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AGUIAR et al. 2020

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RECURRENT MUTATION A235G IN CX3CL1: A NEW GENE IN HB?

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Talita Aguiar, Ph.D - Immunobiology Seminar

BIOLOGICAL FUNCTION OF FRACTALQUINE PROTEIN AND ITS RECEPTOR CX3CR1

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Talita Aguiar, Ph.D - Immunobiology Seminar

IMMUNOHYSTOCHEMISTRY ANALYSIS OF CX3CR1 AND CX3CL1 PROTEINS IN HBs

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Talita Aguiar, Ph.D - Immunobiology Seminar

IMMUNOHYSTOCHEMISTRY - IMMUNO ASSAY

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Talita Aguiar, Ph.D - Immunobiology Seminar

CHEMOKINES AND CANCER

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Talita Aguiar, Ph.D - Immunobiology Seminar

BIMODAL EXPRESSION OF CX3CL1 AND CX3CR1 IN HBs

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Talita Aguiar, Ph.D - Immunobiology Seminar

BIMODAL EXPRESSION OF CX3CL1 AND CX3CR1 IN HBs

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Talita Aguiar, Ph.D - Immunobiology Seminar

RNAseq AND INFLAMMATORY INFILTRATE

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WAITING FOR THE NEXT RESULTS

Talita Aguiar, Ph.D - Immunobiology Seminar

ON GOING - FUNCTIONAL ASSAYS

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Talita Aguiar, Ph.D - Immunobiology Seminar

ACKNOWLEGMENTS

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Talita Aguiar, Ph.D - Immunobiology Seminar

Antibody responses to tumor-associatedadducts in pancreatic cancer

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04

Talita Aguiar, Ph.D - Immunobiology Seminar

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Talita Aguiar, Ph.D - Immunobiology Seminar

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Talita Aguiar, Ph.D - Immunobiology Seminar

“Antibody responses” to “adducts”

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Humoral immunity is the process of adaptive immunity manifested by the production of antibodies by B lymphocytes. It develops in bone marrow. B cells may be triggered to proliferate into plasma cells. Plasma cells produce antibodies. Antibodies are produced when the antigen bonds the B cell receptor (BCR). Some B cells produce memory cells.

Talita Aguiar, Ph.D - Immunobiology Seminar

“Antibody responses” to “adducts”

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Dörner, T. et al. Nat. Rev. Rheumatol 2009

Talita Aguiar, Ph.D - Immunobiology Seminar

“Antibody responses” to “adducts”

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• Natural antibody (Nabs) function in homeostasis and immune protection.

• IgM Nabs prevalent in healthy human serum.

• IgG Nabs increase in pathological situations.

• Nabs react to multiple antigenic structures - POLYREACTIVITY

Talita Aguiar, Ph.D - Immunobiology Seminar

“Antibody responses” to “adducts”

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Front. Immunol., 26 July 2017

- Both murine and human NAbs have been discussed in detail since the late 1960s;

Overview of natural antibodies’ (NAbs) attributes. Graphical representation of the various NAb functions (outside green circle), epitope recognition (inside yellow circle), isotype (inside red circle), and cells shown to produce NAbs (inside blue circle).

Talita Aguiar, Ph.D - Immunobiology Seminar

“Antibody responses” to “adducts”

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Talita Aguiar, Ph.D - Immunobiology Seminar

“Antibody responses” to “adducts”

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Adducts: is a product of a direct addition of two or more distinct molecules, resulting in a single reaction product containing all atoms of all components. The resultant is considered a distinct molecular species. Examples include the addition of sodium bisulfite to an aldehyde to give a sulfonate. It can just be considered as a single product resulting from the direct combination of different molecules which comprises all the reactant molecules' atoms.

Haptens: are small molecules that elicit an immune response only when attached to a large carrier such as a protein; the carrier may be one that also does not elicit an immune response by itself. Once the body has generated antibodies to a hapten-carrier adduct, the small-molecule hapten may also be able to bind to the antibody, but it will usually not initiate an immune response; usually only the hapten-carrier adduct can do this.

Talita Aguiar, Ph.D - Immunobiology Seminar

“Antibody responses” to “adducts”

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Talita Aguiar, Ph.D - Immunobiology Seminar

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Accumulation of adducts in tumor cells? Adducts are immunogenic to B cells?

Talita Aguiar, Ph.D - Immunobiology Seminar

“Antibody responses” to “adducts”

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Talita Aguiar, Ph.D - Immunobiology Seminar

Experimental model - Pilot

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THE TECHNIQUE

Talita Aguiar, Ph.D - Immunobiology Seminar

Principal component analysis of anti-adduct reactivity profiles

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Survival: For all stages combined, the 5-year relative survival rate is 12%. Even for the small percentage (15%) of people diagnosed with localized disease, the 5-year survival rate is only 44%

The incidence of pancreatic cancer has markedly increased over the past several decades. It ranks as the fourth leading cause of cancer death in the United States. Despite the high mortality rate associated with pancreatic cancer, its etiology is poorly understood.

EPIDEMIOLOGY

No tumor-specific markers exist for pancreatic cancer; markers such as serum cancer antigen (CA) 19-9 have low specificity.

The following groups are used to plan treatment:

• Resectable pancreatic cancer
• Borderline resectable pancreatic cancer
• Locally advanced pancreatic cancer
• Metastatic pancreatic cancer
• Recurrent pancreatic cancer

Pancreatic cancer can develop from two kinds of cells in the pancreas: exocrine cells and neuroendocrine cells, such as islet cells. The exocrine type is more common and is usually found at an advanced stage. Pancreatic neuroendocrine tumors (islet cell tumors) are less common but have a better prognosis.

OVERVIEW PANCREATIC CANCER

About 95 out of 100 (95%) of all pancreatic cancers are pancreatic ductal adenocarcinoma (PDAC). PDAC is a type of exocrine pancreatic cancer. It develops from cells lining small tubes in the pancreas called ducts. These carry the digestive juices, which contain enzymes, into the main pancreatic duct and then on into the duodenum (first part of the small intestine).PDAC can grow anywhere in the pancreas, though it is most often found in the head of the pancreas.

OVERVIEW PANCREATIC CANCER

Types of cells in the pancreas

Talita Aguiar, Ph.D - Immunobiology Seminar

RESERACH QUESTION

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Talita Aguiar, Ph.D - Immunobiology Seminar

PATIENTS

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Talita Aguiar, Ph.D - Immunobiology Seminar

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Talita Aguiar, Ph.D - Immunobiology Seminar

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The IgG in the bloodstream is 60 to 70% IgG1, 20 to 30% IgG2, 5 to 8% IgG3, and 1 to 3% IgG4. IgG1 and IgG3 reach normal adult levels by 5 to 7 years of age, while IgG2 and IgG4 levels rise more slowly, reaching adult levels at about ten years of age. Each subclass serves predominantly (but not exclusively) a slightly different function in protecting the body against infection. For example, IgG1 and IgG3 subclasses protect against toxins from bacteria such as diphtheria, tetanus, and viral infections. In contrast, IgG2 predominantly aids in protection against the polysaccharide (complex sugar) capsule of certain disease-producing bacteria such as Streptococcus pneumoniae and Haemophilus influenzae. IgG4 it may also be undetectable in the serum of many normal adult individuals, but it`s high in people with autoimune disease (Zhang H, Li P, Wu D, Xu D, Hou Y, Wang Q, Li M, Li Y, Zeng X, Zhang F, Shi Q. Serum IgG subclasses in autoimmune diseases. Medicine (Baltimore). 2015 Jan;94(2):e387. doi: 10.1097/MD.0000000000000387. PMID: 25590841; PMCID: PMC4602543).

Talita Aguiar, Ph.D - Immunobiology Seminar

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Talita Aguiar, Ph.D - Immunobiology Seminar

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ACCUMULATION OF ADDUCTS IN TUMORS CELLS

Talita Aguiar, Ph.D - Immunobiology Seminar

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​Glucose Phosphorylation​: Glucose and other sugars undergo phosphorylation as the first step of carbohydrate catabolism. Glycolysis begins with the conversion of D-glucose into D-glucose-6-phosphate. ​Protein Phosphorylation​: Protein phosphorylation is an important post-translation modification. In other words, the phosphorylation occurs after a protein is translated from an RNA template. Oxidative Phosphorylation​: Cells use oxidative phosphorylation for storing and releasing chemical energy. ​

Types of Phosphorylation

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Talita Aguiar, Ph.D - Immunobiology Seminar

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PROTEOMICS

PROTEOMICS

what is coming next?

ZORN`S LAB

Talita Aguiar, Ph.D - Immunobiology Seminar

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Exercise 1–"Be the Scientist for One Day: Analyzing ELISA Experiment"

healthy donor 2

healthy donor 1

Patient 2

Patient 1

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Talita Aguiar, Ph.D - Immunobiology Seminar

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break

Talita Aguiar, Ph.D - Immunobiology Seminar

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Exercise2–Immunotherapy Breakthroughs: Communicating Science to the Public

Talita Aguiar, Ph.D - Immunobiology Seminar

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Talita Aguiar, Ph.D - Immunobiology Seminar

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Exercise3–quiz

Thanks!!!!!

Talita Aguiar, Ph.D - Immunobiology Seminar

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