Assessing the Tumor Microenvironment by Recovery of Immune Receptor V(D)J Recombination Reads from Tumor Specimen Exome Files George Blanck, Ph.D. Professor, Molecular Medicine Morsani College of Medicine, USF Immunology Program, Moffitt Cancer Center (not for publication or public web page)
Learning objectives: 1. To appreciate the availability of T-cell receptor recombination information from tumor specimen DNA samples. 2. To understand the correlation between T-cell receptor recombinations, in tumor specimen DNA, and other, clinically relevant information for bladder cancer and kidney renal cell carcinoma. 3. To understand the importance of HLA alleles in assessing the impact of T-cell receptor recombinations from tumor specimen DNA.
Fig. 1. Immune receptor genes recombine during development to generate many different receptor molecules among the B-cells and T- cells, throughout the body, through life, to bind many different antigens, including tumor antigens.
Seven immune receptor genes total: • Three related to antibodies, not further discussed. • Two related to gamma-delta T-cells, not further discussed • Two required for alpha-beta T-cells, the subject of this presentation.
Alpha-beta T-cells: • Most numerous. • Best understood, medically speaking. • Generally target peptide antigen, in the case of tumors, a mutant peptide. • The TRB part of the TRA/TRB receptor is considered most important in antigen binding.
The tumor specimen and the exome • Surgically remove tumor, obtain DNA sequence (all exons = exome), for tumor mutations, which can guide therapy. • Other cells in the specimen, particularly T-cells. • The DNA representing the T-cell receptor can be identified above the tumor DNA “background”.
Fig. 1 again.
Tabulate, millions and millions, along with clinical information: TCGA BLCA Number Reads Clinical status V usage D usage J usage of reads Barcode detected TCCCAGACATCTGTGTAC No subsequent TTCTGTGCCAGCAGTGCC 7 tumor/positive TRBV10-3 TRBD1 TRBJ1-2 TCGA-FD-A5BS CGGACAGGGAAGTATGG CTACACCTTCGGTTCGGG outcome GACCA AGCCCCAACCAGACCTCT No subsequent TRBV27- CTGTACTTCTGTGCCAGC 20 tumor/positive TRBD2 TRBJ2-7 TCGA-FD-A5C1 AGTTTATCGGGCGGGGG 01 AGTATACGAGCAGTACTT outcome CGGGC
Results 1. For bladder cancer, the more TRB recombination reads, the better the outcome. 2. For melanoma and renal cell carcinoma, the more TRA and TRB reads, the higher the levels of immune checkpoint protein expression. 3. For certain cancers, the combination of usage of a particular V or J segment, by T-cells in the tumor microenvironment, and a particular HLA type, corresponds to a dramatic survival distinction.
Data collection redacted in anticipation of separate publication.
Fig 3. The T-cell receptor binds to antigen by simultaneously binding the HLA molecules on other cells.
References for preceding slides, results • Anne Mai et al submitted • Kendall Clark et al in prep
The future: • Exome detectable TcR recombinations, that correlate with survival or immune checkpoint protein expression are likely to be of use in settings where cost-efficiency is paramount, or as a confirmation. • Linking TcR gene segment usage to HLA alleles for prognosis may be doable, routinely, with exome based recovery of TcR recombinations, particularly in settings where cost-efficiency is paramount; or, TcR segment usage may be more reliably assessed with other methods, for matching to HLA alleles.
Question: What is the surrogate for detection of tumor microenvironment T-cells, when relying on an exome file? A. HLA allele sequence B. Oncogene mutations C. PD1 D. V-J recombination read
USF research group USF research computing Wei Lue Tong Dr. Timothy Fawcett Yaping Tu Blake Callahan Anne Mai Jacob Kinskey Dhiraj Sikaria Seyed Ahmad Falasiri Diana Fisler Moffitt Collaborators John Yavorski Tasnif Rahman Wade J. Sexton Kendall Clark Domenico Coppola Tommy Gill Minjung Kim Jay Patel
12/07/2011 Alzheimers Disease Risk Gene CLU and White Ma;er Integrity Meredith Braskie Ringman & Thompson labs Turken Award for Alzheimers
252 views • 8 slides
Antagonistic Interactions Among Stripe and Stem Rust Resistance QTLs in Wheat Abdulqader Jighly The International Center for Agricultural Research in the Dry Areas (ICARDA) Borlaug Global Rust Initiative Technical Workshop Obregon - Mexico,
260 views • 24 slides
Genetics Core Concepts Mendels Law of Segregation states that there are two alleles for every gene determining a specific characteristic, and these alleles are segregated into separate gametes during reproduction. When the 2 different
786 views • 25 slides
DNA Short Tandem Repeats Organism DNA Short Tandem Repeats Organ DNA Short Tandem Repeats Cell Weights 1kg a bag of sugar 1g paper clip 1mg (milligram) 0.001g brain of a bee 1g (microgram) 0.000001g weight of a
1.38k views • 102 slides
TWO INTERESTING CASES OF MOLECULAR DIAGNOSIS FOR HHT: LOW-LEVEL MOSAICISM AND ABNORMAL SPLICING OF ACVRL1 Christopher Trevors, MSc, CGC June 10, 2017 Disclosures: Full time paid employee of Impact Genetics, Dynacare, LabCorp Impact Genetics
307 views • 15 slides
Demystifying DNA Demystifying DNA What is it? How do I get it? What is it? How do I get it? How do I get rid of it? How do I get rid of it? Alissa Bjerkhoel Litigation Coordinator, California Innocence Project Panel Attorney,
1.61k views • 124 slides
Building the Best UC TCA Submission - with a Community College Perspective Nancy Purcille, UCOP Jennifer Forsberg, UCOP Deborah McCaskey, UCOP Steve Pantell, Merritt College Annual CIAC Conference March 26-27, 2015 Berkeley, CA The TCA
443 views • 11 slides
MENDELIAN RANDOMIZATION Maria Carolina Borges Research Fellow MRC Integrative Epidemiology Unit University of Bristol UK Outline Motivation Assumptions One-sample MR Two-sample MR Recent extensions MR-Base MOTIVATION
1.13k views • 64 slides
HOPE( s) for Qantitative Environm ental Microbiological Studies Wen-Tso Liu Division of Environmental Science & Engineering Molecular Biological Tools (MBT) Sample collection & Challenges Nucleic Acid based concentration Whole
292 views • 15 slides
Modulating the Therapeutic Microenvironment Using Nanostructured Materials Tej ejal A l A. Des esai, i, Ph PhD Ernest st L L Pr Prien Professo essor and C nd Chair Direc ector, UCSF E F Engineer eering and nd Appl pplied ed S
836 views • 25 slides
The application of DNA markers to monitoring adaptation and migration of forest tree species Michele Morgante Rome, 22 February 2008 WHAT IS GENETIC VARIABILITY? GENETIC VARIATION = SEQUENCE VARIATION CHR-A cAAaTTATTA ATAATTTGGT
307 views • 20 slides
Rebekah A. Mohn Miami University, Oxford, Ohio firstname.lastname@example.org Mentor: Christine E. Edwards A separately evolving metapopulation lineage where lineage refers to an ancestor -descendent lineage. (De Queiroz, 2007) De Queiroz.
430 views • 24 slides
Allergy Client Presentation 1 2 3 Allergens are normally harmless substances that don't cause an issue to other animals, however, in pets with allergies, they cause an abnormal response. 4 Bacteria and yeast can act as allergens too - in
248 views • 6 slides
INFORMATION REQUIREMENTS OF ALLERGIC CONSUMERS WHEN EATING OUT: A RESEARCH PERSPECTIVE Julie Barnett Professor of Health Psychology University of Bath The Project and the Team THE PREFERENCES OF THOSE WITH FOOD ALLERGIES AND/OR INTOLERANCES
403 views • 19 slides
Precautionary Allergen Labelling Lynne Regent Anaphylaxis Campaign CEO @LynneRegentAC About the Anaphylaxis Campaign The only UK wide charity solely focused on supporting people at risk of severe allergic reactions Membership service
713 views • 18 slides
Did you know a food allergy affects the immune system? ARMY OF WHITE BLOOD CELLS ANTIBODIES ARE ARROW LIKE WEAPONS GERM Inside your body are things called white blood cells that fight germs and help us from becoming sick. These
500 views • 20 slides
Allergy Therapeutics Interim results for the six months ending 31 December 2017 Delivering on our strategy three areas for growth March 2018 Disclaimer The information contained in this presentation (Presentation) is being supplied to
526 views • 36 slides
Interim Results for the six months ending 31 December 2019 Presentation and global webcast, 4 March 2020 Manuel Llobet , Chief Executive Officer Nick Wykeman , Chief Financial Officer Alan Bullimore , Head of Communications & Market
1.1k views • 25 slides
Nutrition Facts Labeling Understanding the Nutrition Facts Label Julie Bush & Rebekah Spetnagel Food & Drug Administration (FDA) Enforces the Federal Food, Drug and Cosmetic Act Five Centers including Center for Food
669 views • 44 slides
Non-Confidential Sementis: Revolutionizing the Global Vaccine Industry Oct 2017 www.sementis.com.au Version: 171017PH Disclaimer October 2017 This presentation is issued by Sementis Limited ACN 138 550 811 ( Sementis ) in order to provide
585 views • 54 slides
Canadian Food Labelling Requirements January 2018 The Canadian Food Inspection Agency Food safety is the CFIA's top priority. Activity range: Inspection of facilities (federally-registered & NFR), undertaking 1. preventive measures using
1.13k views • 94 slides
Food Handler Training Food Handler Training Food Handler Training Food Handler Training Online Presentation Online Presentation Online Presentation Online Presentation Outline Outline Public Health Laws Wash, Rinse and Sanitize
852 views • 58 slides
Managing Life - Threatening Allergies in School Allergy Basics The role of the immune system is to protect the body from germs and disease An allergic reaction is an abnormal response of the immune system to contact with a substance (the
344 views • 16 slides
FOOD ORAL IMMUNOTHERAPY A New Option for the Treatment of Food Allergies EAT FEARLESSLY Food Oral Immunotherapy (OIT) is lifechanging for families with food allergies It is available at about 50 US allergy practices, and it has been offered
551 views • 14 slides