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社会、健康、医療に貢献するための学際的公衆衛生学・疫学の未来
Kyoto University School of Public Health (35 min)
Shuji Ogino, MD, PhD, MSChief of Molecular Pathological Epidemiology (MPE)
Professor (Pathology & Epidemiology)Brigham and Women’s HospitalDana-Farber Cancer Institute
Harvard Medical SchoolHarvard T.H. Chan School of Public Health
Broad Institute of MIT and Harvard
CRC = colorectal cancer
MPE = molecular pathological epidemiology
MSI = microsatellite instability(hypermutator, high neoantigen load)(Immune checkpoint inhibitor works for MSI-high solid tumors)
Epidemiology
One Field MPE1 + 1 100
Big Synergism
Molecular Pathology
Tumorcells
Obesity EnvironmentDiet
Genetic variation
Immune cells
Microbiome
Ogino et al. Gut 2018Ogino et al. Lancet 2018
Drug
Tumorcells
Obesity EnvironmentDiet
Genetic variation
Immune cells
Microbiome
Drug
Complex problems necessitateexpertise in multiple fields
Ogino et al. Gut 2018Ogino et al. Lancet 2018
Tumorcells
Obesity EnvironmentDiet
Genetic variation
Immune cells
Microbiome
Drug
Exposures can easily influence tumor - immune interactions
Ogino et al. Gut 2018Ogino et al. Lancet 2018
Pathology methods
Epidemiologymethods
Integrative MPE
Bioinformatics methods(machine / deep learning)
Immune response
Mutated peptides(neoantigens)
CD274 (PD-L1)expression
Tumor - Immune Interactions
Immune response FOXP3+ Treg
Masugi et al. Gut 2016
CD274 (PD-L1)
Mutated peptides(neoantigens)
Tumor - Immune Interactions
2+
Surv
ival
pro
babi
lity
CRC-specific survival (years)
P < 0.0001
3+
0
1.0
0.8
0.6
0.4
0.2
0.0
1+
Immune cells in tumor microenvironment = best prognostic biomarker (why not clinical decision making?)
Multiplex immunofluorescence
CD3 (brown), CD4 (yellow), CD8 (purple), CD45RO (green), FOXP3 (orange)
Borowsky, et al.
Immunology-MPEStudies
Why are there names of fields (such as “epidemiology”)?
Colon has rich microbiota & immune tissueKnown risk (or protective) factorsBest model for immunology-MPE
Nurses’ Health Study (121,700 women)
Health Professionals Follow-up Study (51,500 men)
Prospective Cohort Studies
1976
1986
Nurses’ Health Study(121,700 women)
Health Professionals Follow-up Study (51,500 men)
Diet, lifestyle, environment, genetics, plasma metabolomics, etc.
Nurses’ Health Study(121,700 women)
Health Professionals Follow-up Study (51,500 men)
Diet, lifestyle, environment, genetics, plasma metabolomics, etc.
1,600 colorectal cancers
1,000 polyps with tissue
Molecular pathology (whole exome sequencing,RNA-sequencing)Tissue microbiotaImmune cells
Mortality
Exposure
1,600 CRC cases
Normal colon
Subtype A
Subtype B
Mor
talit
y
Exposure
MPE analyses
170,000 persons
Exposure
1,600 CRC cases(~2,000 CRC cases without tissue)
Utilize excluded cases to get better data
Normal colon
Subtype A
Subtype B
Mor
talit
y
Exposure
170,000 persons
Hypothesis: (1) Changes caused by the exposure
(2) Changes confer growth advantages
Liu et al. Eur J Epidemiol 2018
Preventive effect of colonoscopy differsby microsatellite instability (MSI) status
Nishihara et al. N Engl J Med 2013
Colonoscopy screening
MSI cancer
non-MSI cancerNormal colon
Preventive effect of colonoscopy differsby microsatellite instability (MSI) status
Nishihara et al. N Engl J Med 2013
Colonoscopy screening
MSI cancer
non-MSI cancerNormal colon
MPE can advance precision prevention(smokers have higher risk for MSI cancer)
Marine -3 polyunsaturated fatty acids(rich in fish oil)
• (?) reduce CRC risk• Marine -3 fatty acids can inhibit regulatory
T cells stimulate effector T cells
Immune response
Mutated peptides(neoantigens)
Tumor cells
FOXP3+ Treg
Immune response
Mutated peptides(neoantigens)
Tumor cellsMarine -3fatty acids
FOXP3+ Treg
-3 fatty acids
CRC subtypes
Normal colon
FOXP3+ cell-high
FOXP3+ cell-low
0
0.5
1
1.5
2
Ref
Pheterogeneity = 0.006
Marine ω-3 fatty acid intake
Ptrend < 0.001
Ref
Mul
tivar
iate
Rel
ativ
e R
isk
FOXP3+ cell-low CRC FOXP3+ cell-high CRC
low high low high
Song et al. JAMA Oncol 2016
PUFA can reduce T-cell suppressive activity of FOXP3+ cell, leading to CD4+ T cell proliferation
Song et al. JAMA Oncol 2016
CD
4+ c
ell p
rolif
erat
ion
(%)
PUFA concentration
Immune response
Mutated peptides(neoantigens)
Tumor cellsMarine -3fatty acids
FOXP3+ Treg
Exposures (or risk factors) influence risk of CRC immune subtype
• Marine -3 PUFAs (Song. JAMA Oncol 2016)• IBD risk SNP (Khalili. Carcinogenesis 2015)• Vitamin D (Song. Gut 2016)• Aspirin (Cao. Gastroenterology 2016)• Inflammatory diet (Liu. Gastroenterology 2018)• Smoking (Hamada. JNCI 2018)• Calcium intake (Wang. Cancer Prev Res in press)
Microbiology-MPE(essential for
Immunology-MPE)
Tumorcells
Obesity EnvironmentDiet
Genetic variation
Immune cells
Microbiome
Ogino et al. Nature Rev Clin Oncol 2011Ogino et al. Gut 2018Ogino et al. Lancet 2018
Drug
Challenges in microbiome research
• Which microorganism causes cancer?
• Experimental models have different microbiome and immune system
• We focus on tumor tissue microbiota
Fusobacterium nucleatum in CRC tissue
Immunosuppressive lower T cellsHigher stage shorter survivalMSI-highGo with metastasis
Mima et al. JAMA Oncol 2015Mima et al. Gut 2016Bullman et al. Science 2017
Diet Gut microbiota Cancer
Diet Gut microbiota Cancer
Prudent diet(vegetables, whole grains, beans, fiber)
Good microbiota( bad bacteria)
Fusobacteriumnucleatum(+) CRC
Pheterogeneity = 0.009
Ptrend = 0.003
Prudent diet score (quartiles)
F. nucleatum (-) CRC F. nucleatum (+) CRC
RefRef
Mul
tivar
iate
Rel
ativ
e R
isk
Mehta et al. JAMA Oncol 2017
low high low high
Prudent diet (vegetables, whole grains, beans)
CRC subtypes
Normal colon
F. nucleatum (+)
F. nucleatum (-)
Mehta et al. JAMA Oncol 2017
Prudent diet microbiota prevention
Causal inference - MPE
Statistical methodsin MPE
Immunology-MPEMicrobiology-MPE
Network scienceMPE
Molecular Pathological
Epidemiology(MPE)
Pharmaco-MPE
Etc.
Nutritional MPE
MPE can change our concept on scientific fields (expand, but not narrow down)
Ogino et al. Annu Rev Pathol 2018
5th
June 2020, Boston, USA
Free registrationOpen to public
www.mpemeeting.org
Summary• Immunology-MPE (Molecular Pathological
Epidemiology) can provide new insights– Exposures can easily influence microbiota–
tumor–immune interactions– Immunoprevention & therapy (using nutrients &
lifestyle)• Exposures influence immunotherapy• MPE is making new frontiers
– There are widely open opportunities!
Summary 2• Let’s do “immunology-MPE” and
“microbiology-MPE” studies!
Acknowledgements (I cannot list everyone)• Yale Cancer Center
– Charles Fuchs• Dana-Farber Cancer Institute
– Marios Giannakis– Matthew Meyerson– Gordon Freeman– Catherine Wu– Jeffrey Meyerhardt– Levi Garraway
• Mass General Hospital– Andrew Chan
• Fred Hutchinson CRC– Ulrike Peters– Amanda Phipps
• UCLA / Parker Institute– Antoni Ribas– Catherine Grasso
• Harvard T.H. Chan School of Public Health / CDNM, Brigham and Women’s Hospital– Edward Giovannucci– Walter Willett – Lorelei Mucci– Meir Stampfer – Tyler VanderWeele– Mingyang Song– Kana Wu– Molin Wang– Xuehong Zhang– Curtis Huttenhower– Wendy Garrett
• Brigham & Women’s (Pathology)– Scott Rodig– Jonathan Nowak– Reiko Nishihara
Acknowledgements #2• NHS (n=121,700), NHS II (n=116,600)
and HPFS (n=51,500) prospective cohort participants
• Various US hospitals/pathology departments for proving medical records and tissue specimens
Funding• NIH/NCI• Bennett Family Fund• Dana-Farber Harvard Cancer Center• Entertainment Industry Foundation
National Colorectal Cancer Research Alliance (NCCRA)
• Japan Society for Promotion of Science
• Japanese Society for Multidisciplinary Treatment of Cancer
• Uehara Memorial Foundation• Project P Fund• DFCI Friends
• The Ogino MPE Lab – Reiko Nishihara (Co-PI)– Jonathan Nowak (faculty)– Kota Arima– Annacarolina da Silva– Andressa Dias Costa– David Drew– Simeng Gu– Chunguang Guo– Carino Gurjao– Kenji Fujiyoshi– Koichiro Haruki– Xiaosheng He– Junko Kishida– Iny Jhun– Mai Chan Lau– Peilong Li– Juha Vayrynen– Sara Vayrynen– Tyler Twombly– Melissa Zhao
Causal inference - MPE
Statistical methodsin MPE
Immunology-MPEMicrobiology-MPE
Network scienceMPE
Molecular Pathological
Epidemiology(MPE)
Pharmaco-MPE
Etc.
Nutritional MPE
MPE can change our concept on scientific fields (expand, but not narrow down)
Ogino et al. Annu Rev Pathol 2018