yoshihiro ohue, md, phd - uminatdd-frm.umin.jp/slide/26/ohue.pdfcomprehensive analysis of tumor...
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Laboratory HeadDivision of Cancer Immunology, National Cancer Center, Japan
Yoshihiro Ohue, MD, PhD
Immunological resistance to Immune Checkpoint Inhibitor
The 26th Anti-Cancer Drug Development Forum
February 16th , 2019, Japan
Disclosure Information
Div. of Cancer Immunology, National Cancer Center
Yoshihiro Ohue, M.D., Ph.D.
I have no financial relationships to disclose.
Cancer Immunotherapy～the long journey to success～
3
William Coley
(1862-1936)2018年
Paul Ehrlich
(1854-1915)
Current status of immunity checkpoint inhibitors
No dramatic therapeutic effect except anti-PD-1 and anti-CTLA-4
Activation
pathway
Inhibitory
pathway
Blocking antibodyAgonistic antibody
T-cell activation
. Curr Opin Immunol 2016
48yrs, female, NSCLC (Ad) cT3N2M1b stage IVa,
EML4-ALK fusion (+)At diagnosis
6th linePre anti-PD-1
Post anti-PD-1
2018.62015.11 2017.2
9th linePre anti-PD-1
Post anti-PD-1
48yrs, male, NSCLC (Ad) cT1bN2M1b stage IVa,
EGFR mutaion (+)
PeripheralLocal site
Immune cell
infiltration
fibroblast
Lymphatic endothelium
Endothelium
CD8+T cell
CD4+ T cell
Regulatory T cell
MDSC/MΦ
Regulatory B cell
Tumor microenvironment
Cause of immunological resistance to anti-tumor immunity
Immunological
Resistance
Lack of
inflammation
Inadequate
antigenicity
Suppressor
immune cells
Compensatory
checkpoint
Suppressive
stroma fraction
Tumor intrinsic
pathway
Treg
Breg
MDSC
TAM
Deletion in TAP, β2M
Loss of HLA
Low TMB
Mutation in IFNg signaling
Metabolite/Cytokine dysregulation
Downregulation of adhesion molecule
Oncogenic signaling
Epigenetic silencing
CAFs
Endothelium
Lymphatic endothelium
PD-1, TIM-3, LAG-3, TIGIT, VISTA
Correlation of PD-L1 and Galectin-9 expression, and TIL
TILPBMC
22 0
76 2
52 25
20 3
Gated on CD8
PD
-1
TIM-3
Flow cytometry
Ohue Y, et, al. Cancer Immunol Res. 2016
Analysis of each fraction
%fr
equency
%K
i-67
%A
nnexin
V%
CD
27
PD
-1-
TIM
-3-
PD
-1+
TIM
-3-
PD
-1-
TIM
-3-
PD
-1+
TIM
-3-
PD
-1+
TIM
-3+
PD
-1+
TIM
-3+
PD
-1-
TIM
-3+
PD
-1-
TIM
-3+
CD8
PBMC TIL
0
10
20
020406080
100
020406080
100
010
30
50
20
40
P＜0.01
P＜0.01
P＝0.02
P=0.02
P＜0.01
P<0.01
P=0.01
P=0.02
Differentiation
Proliferation
Apoptosis
Antibody blocking
Apoptosis by galectin-9
T-cell apoptosis by soluble Galectin-9
Gal-9 (pg/ml)
%A
nn
exin
V
11
13
15
25
51
0
38
75
150
300
Gal-9 (pg/ml)
0
20
40
60
0 38 75 150 300
%ce
ll d
ea
th
0 38 75 150 300
0
20
30
40
10
Gal-9 (pg/ml)
**
%Annexin V
Non-treat
Gal-9
Gal-9 + α-Gal-9
Gal-9 + Ctr-IgG
Gal-9 + α-TIM-3
9
41
40
17
15
17Gal-9 + α-Gal-9
+ α-TIM-3
Gal-9
α-Gal-9Ctr-IgG
α-TIM-3
-
－-
-
＋
－-
-
＋
－＋
-
＋
＋-
-
＋
--
＋
＋
＋-
＋
0
20
30
40
10
50
%A
nn
exin
V ******
***
%Annexin V
Ohue Y, et, al. Cancer Immunol Res. 2016
Release of soluble Galectin-9 from tumor cells
**** p < 0.0001
PC-9
(EGFRmt)
OU-LC-SK
(EGFRwt)
Afatinib - + - +
Ga
l-9
(pg/m
l)
0
5
10
15
****
A BGalectin-9 expression%
of M
ax
Surface Intracellular
0 10 10 10 102 3 4 5
53
0 10 10 10 102 3 4 5
100
Cell line (OU-LC-SK)
Lung cancer tissue
Ohue Y, et, al. Cancer Immunol Res. 2016
***
Pleural
effusion
serum
HD Pt
Ga
l-9
(pg/m
l)
0
1000
1800
2000
800
600
400
200
Galectin-9
in clinical samples
C
Involvement of immune checkpoint molecules
at the late phase of disease progression
12Ohue Y, et, al. Clin Cancer Res. 2014
IL-2IFN-γ etc…
IL-4IL-5 etc…
Antibody
Tumor
FcR
CD4 T-cell CD8 T-cell
APC
B-cell
PD-1
PD-L1MHC
CD8CD28
CTLA-4
MHC
CD4CD80/86
apoptosisapoptosis
TIM-3TIM-3
Galectin-9
Ohue Y, et, al. OncoImmunol. 2014
Tumor immune microenvironmentTumor immune microenvironment
CD4 CD8
B cell
Treg
NK cellMyeloid cell0 103 104
0
10
310
410
5
0.2 0.2
61.0 5.5 33.1
I
IIIIIIV, V
VI
FoxP3
CD
45R
A
Fr. I:Fr. II:Fr. III:
Naive Treg cellsEffector Treg cellsNon-Treg cells
Comprehensive Analysis of Tumor Immunity
Acknowledgements
15
Kawasaki Medical SchoolDr. Eiichi Nakayama Dr. Mikio Oka
Dr. Hiroyoshi Nisikawa