Immunobiology Seminar Fordham

Intersecting Frontiers: Uniting Genetic,Epigenetic and translational Immunology

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

START

Who I am?

@sciencewithcoffe

Talita Aguiar, Ph.D - Immunobiology Seminar

Biomedical science

MBA in Health Management, Innovation, and Services

Ph.D in molecular oncology - BRAZIL

PHD INTERSHIP TEXAS CHILDREN`S HOSPITAL

Postdoctoral Research Scientist ny

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

01

cancer

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

WHY SHOULD WE STUDY CANCER?

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

The Emperor of All Maladies

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

Urbanization and the "modern lifestyle"

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

WHY SHOULD WE STUDY CANCER?

@sciencewithcoffe

Talita Aguiar, Ph.D - Immunobiology Seminar

WHY SHOULD WE STUDY CANCER?

@sciencewithcoffe

Talita Aguiar, Ph.D - Immunobiology Seminar

WHY SHOULD WE STUDY CANCER?

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

@sciencewithcoffe

Talita Aguiar, Ph.D - Immunobiology Seminar

02

PEDIATRIC TUMORS

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

CHILDHOOD CANCER: A PUBLIC HEALTH PROBLEM?

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?

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

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

PREVALENCE

Prevalence of pediatric cancers (0-19 years)

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

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

INCIDENCE, MORTALITY AND MORE

1430 died by the disease

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

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

"Beyond, pero no much" biological science

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

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

"Beyond, pero no much" biological science

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

@sciencewithcoffe

"Beyond, pero no much" biological science

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

@sciencewithcoffe

"Beyond, pero no much" biological science

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

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

"Beyond, pero no much" biological science

Most standard childhood cancer treatments are decades old

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

THE ATTENTION FOR RARE DISEASES

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

THE ATTENTION FOR RARE DISEASES

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

MULTIDISCIPLINARITY

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

SYMPTONS

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

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

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

RISK FACTORS

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

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

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

WHY CHILDREN ALSO HAVE CANCER?

Hallmarks of cancer

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

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

WHY CHILDREN ALSO HAVE CANCER?

Somatic mutations

GRÖBNER et al. 2018

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

PEDIATRIC MATCH

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

03

GENOMIC ALTERATIONS OF HEPATOBLASTOMA

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

EMBRYONAL TUMOR OF LIVER

ZORN et al. 2008

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

HEPATOBLASTOMA (HB)

• 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

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

HB has the lower number of somatic mutations

GRÖBNER et al. 2018

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

HB: SOMATIC MUTATIONS

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

@sciencewithcoffe

HB: SOMATIC MUTATIONS

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

HUMAN GENETICS LAB (IB/USP)

• 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

@sciencewithcoffe

PATIENTS

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

SOMATIC MUTATIONS

AGUIAR et al. 2020

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

EXOME SEQUENCING

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

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

AGUIAR et al. 2020

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

BIOLOGICAL FUNCTION OF FRACTALQUINE PROTEIN AND ITS RECEPTOR CX3CR1

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

IMMUNOHYSTOCHEMISTRY ANALYSIS OF CX3CR1 AND CX3CL1 PROTEINS IN HBs

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

IMMUNOHYSTOCHEMISTRY - IMMUNO ASSAY

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

CHEMOKINES AND CANCER

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

BIMODAL EXPRESSION OF CX3CL1 AND CX3CR1 IN HBs

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

BIMODAL EXPRESSION OF CX3CL1 AND CX3CR1 IN HBs

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

RNAseq AND INFLAMMATORY INFILTRATE

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

WAITING FOR THE NEXT RESULTS

ON GOING - FUNCTIONAL ASSAYS

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

ACKNOWLEGMENTS

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

04

Antibody responses to tumor-associatedadducts in pancreatic cancer

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

“Antibody responses” to “adducts”

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

“Antibody responses” to “adducts”

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

@sciencewithcoffe

“Antibody responses” to “adducts”

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

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

“Antibody responses” to “adducts”

• 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

@sciencewithcoffe

“Antibody responses” to “adducts”

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).

Front. Immunol., 26 July 2017

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

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

“Antibody responses” to “adducts”

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

“Antibody responses” to “adducts”

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.

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.

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

“Antibody responses” to “adducts”

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

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

Experimental model - Pilot

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

THE TECHNIQUE

Principal component analysis of anti-adduct reactivity profiles

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

EPIDEMIOLOGY

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.

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%

OVERVIEW 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.

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

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

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.

Types of cells in the pancreas

RESERACH QUESTION

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

PATIENTS

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

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

@sciencewithcoffe

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

ACCUMULATION OF ADDUCTS IN TUMORS CELLS

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

Types of Phosphorylation

​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. ​

@sciencewithcoffe

PROTEOMICS

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

PROTEOMICS

what is coming next?

ZORN`S LAB

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

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

healthy donor 1

Patient 1

Patient 2

healthy donor 2

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

break

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

Exercise2 – Immunotherapy Breakthroughs: Communicating Science to the Public

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

Exercise3 – quiz

Talita Aguiar, Ph.D - Immunobiology Seminar

@sciencewithcoffe

Thanks!!!!!

@sciencewithcoffe

Talita Aguiar, Ph.D - Immunobiology Seminar