biomarkers from the tumor microenvironment: are...
TRANSCRIPT
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Biomarkers from the Tumor Microenvironment: Are they Useful?
George Coukos, M.D, Ph.D.Director, Gynecologic Malignancy Research Programs
University of Pennsylvania
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Biomarkers from the tumor microenvironment
• Tumor microenvironment events affect tumor outcome
• Tumor microenvironment events are identifiable through cellular or molecular markers
• Markers are mechanistically relevant• Modulation of tumor microenvironment affects
tumor outcome• Modulation of tumor microenvironment can be
traced through these markers
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Tumor Microenvironment
Cancer CellsCancer Cells
Immune Cells
Stroma Cells
Endothelial Cells
The Reductionist View A Heterotypic Cell Biology
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Do Leukocytes Play a Role in Ovarian Cancer ?
CD45 CD11c CD3
Cellular BiomarkersIntratumoral T cellsT regulatory cellsVascular leukocytes
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CD3+
Intratumoral T cells
54.8%
38.7%
6.5%N=174
Zhang et al., NEJM 2003
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Impact of TILs on Outcome in Ovarian CancerStage III/IV – All patients (n=174)
PFS Survival
+ TILs- TILs
N=174
Zhang et al., NEJM 2003
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TILs correlate with tumor-reactive PBLs
Patient No. ELISPOT TILs
OV22 + +
OV23 -/+ +
OV24 -- --
OV26 -- --
OV27 + +
OV28 -- --
OV29 + +
OV31 + --
OV32 + +
OV34 -- --
P < 0.045
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Intratumoral T cells exhibit oligoclonal expansion
A
B D
C
Vβ8
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TILs Recognize TAAs in Ovarian Cancer
CD
8S
SC
CD
14-C
D4
Her2-369-APCEBV-PE TERT-PE Her2-689-PETax-PE
CD8FSC
.
Tumor Biopsyor Ascites
Disassociation
PE
APC-CY7
PE-Cy5
APC-Cy7
+Flow Cytometric
Analysis
Antigen Specific TILs
Cy5
PE
FreshlyIsolated
.
Bob Vonderheide
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Proposed Biomarkers for Tumor Immune Surveillance
• Intratumoral CD8+ T cells
• IFN-γ, MIG, IP-10
• pLCK, pZap-70
• NKG2D ligands
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CD4+CD25+ Treg
R3 live cells/CD3+
Ascites panel.019
1 10 100 1000 10000
FL2-H: CD25 PE
1
10
100
1000
10000
FL4-H: CD4 APC
R3 live cells/CD3+ Ascites panel.018
1 10 100 1000 10000 FL2-H: CD25 PE
1
10
100
1000
10000
FL4-H: CD8 APC
26.3
CD25
CD8 CD4
Numbe r of CD4+ cells added
0 1000 5000 10000 200000
20
40
60
80
100
120
CD4+C D25+
CD4+C D25-
B
% o
f M
axim
um
Res
pons
e
Numbe r of CD4+ cells added
0 1000 5000 10000 200000
20
40
60
80
100
120
CD4+C D25+
CD4+C D25-
B
% o
f M
axim
um
Res
pons
e
Numbe r of CD4+ cells added
0 1000 5000 10000 200000
20
40
60
80
100
120
CD4+C D25+
CD4+C D25-
CD4+C D25+
CD4+C D25-
B
% o
f M
axim
um
Res
pons
e
CD4+CD25+
CD4+CD25-
CTLA-4
CTLA-4
CD4
CD
25
CD4+CD25+
CD4+CD25-
CTLA-4
CTLA-4
CD4
CD
25
Woo et al., Cancer Res 2002; J Immunol 2003
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Regulatory CD4+CD25+ T Cells in Ovarian Cancer
0
10
20
30
40
50
0 5 15 25 35 45 55 65 75 85 95
mRNA FOXP3 (M idpoint)
Pe
rce
nt
Curiel, Coukos et al., Nature Med 2004
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Proposed Biomarkers for Tolerance
• CD4+CD25+ T cells
• foxP3
• GITR, CTLA-4
• Neuropilin-1
• IL-10, TGF-β• PD-1
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CD11c+ cells with DC / endothelial phenotype and
vasculogenic competence
Vascular Leukocytes
Conejo-Garcia et al., Nature Med 2004
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Ascites
Endothelial cells and vascular leukocytes coexist in human ovarian cancer
Conejo-Garcia et al., Blood 2004
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Proposed Biomarkers for Angiogenesis
• CD45+CD11c+VE-cadherin+ cells
• VEGF-A
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Activity of Biological Therapy in Ovarian Cancer
Hodi et al., PNAS 2003
0 1 2 3 4Years
0.2
0.4
0.6
0.8
1.0
PF
S (
%)
CP (n=68)
CP+IFN-γ (n=65)
P=0.031
Conejo-Garcia et al. Nat Med. 2004Windbichler GH, et al. Br J Cancer. 2000
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Acknowledgements
Coukos Lab•Lin Zhang•Jose R. Conejo-Garcia•Fabian Benencia•Ron Buchanovitz•Alisha Mohamed•Cecilia Coureges•Heidi Gray•Ann Jenkins•David Holtz•Eugene Kang•Cristina Vezzani•Giorgia Regnani•Shun Liang•Karen Nishida
Dept. Biostatistics•Phyllis Gimotty
Abramson•Carl June
U. of Torino•Dionyssis Katsaros•Marco Massobrio