Oncotarget, Advance Publications 2016
www.impactjournals.com/oncotarget/
Cross-platform comparison of independent datasets identifies an immune signature associated with improved survival in metastatic melanoma Ricardo D. Lardone1, Seema B. Plaisier1, Marian S. Navarrete1, Jaime M. Shamonki2, John R. Jalas3, Peter A. Sieling1,*, Delphine J. Lee1,* 1
epartment of Translational Immunology, Dirks/Dougherty Laboratory for Cancer Research, John Wayne Cancer Institute, D Santa Monica, CA 90404
2
California Cryobank, Los Angeles, CA 90025
3
Department of Pathology at Providence Saint John’s Health Center, Santa Monica, CA 90404
*
These authors have contributed equally to this work
Correspondence to: Delphine Lee, e-mail:
[email protected] Ricardo Lardone, e-mail:
[email protected] Keywords: metastatic melanoma, tumor immunology, bioinformatics, rank-rank hypergeometric overlap, B cells Received: November 02, 2015 Accepted: January 29, 2016 Published: February 13, 2016
ABSTRACT Platform and study differences in prognostic signatures from metastatic melanoma (MM) gene expression reports often hinder consensus arrival. We performed survival/ outcome-based pairwise comparisons of three independent MM gene expression profiles using the threshold-free algorithm Rank-Rank Hypergeometric Overlap analysis (RRHO). We found statistically significant overlap for genes overexpressed in favorable outcome (FO) groups, but no overlap for poor outcome (PO) groups. This “favorable outcome signature” (FOS) of 228 genes coinciding on all three overlapping gene lists showed immune function predominated in FO MM. Surprisingly, specific cell signature-enrichment analysis showed B cell-associated genes enriched in FO MM, along with T cell-associated genes. Higher levels of B and T cells (p5
2.77E-16
420
34
4.37
+
>5
2.96E-16
3211 625
90 40
33.43 6.51
+ +
2.69 >5
3.86E-16 4.02E-16
257
28
2.68
+
>5
4.06E-16
258
28
2.69
+
>5
4.49E-16
258
28
2.69
+
>5
4.49E-16
236
27
2.46
+
>5
5.78E-16
3252
90
33.86
+
2.66
8.98E-16
266
28
2.77
+
>5
9.84E-16
120
21
1.25
+
>5
2.01E-15
482
35
5.02
+
>5
2.31E-15
220 220 222
25 25 25
2.29 2.29 2.31
+ + +
>5 >5 >5
1.68E-14 1.68E-14 2.07E-14
334
29
3.48
+
>5
3.35E-14
4866
110
50.66
+
2.17
3.56E-14
4866 228 4465
110 25 104
50.66 2.37 46.48
+ + +
2.17 >5 2.24
3.56E-14 3.81E-14 7.39E-14
188
23
1.96
+
>5
8.47E-14
1
signaling pathway GO:0048518~positive regulation of biological process GO:0048584~positive regulation of response to stimulus GO:0007154~cell communication GO:0034109~homotypic cell-cell adhesion GO:0016337~single organismal cellcell adhesion GO:0050870~positive regulation of T cell activation GO:0034097~response to cytokine stimulus GO:1903039~positive regulation of leukocyte cell-cell adhesion GO:0034112~positive regulation of homotypic cell-cell adhesion GO:0022409~positive regulation of cell-cell adhesion GO:0098602~single organism cell adhesion GO:0065007~biological regulation GO:0002768~immune responseregulating cell surface receptor signaling pathway GO:0071345~cellular response to cytokine stimulus GO:0030155~regulation of cell adhesion GO:0002757~immune responseactivating signal transduction GO:0002764~immune responseregulating signal transduction GO:0050852~T cell receptor signaling pathway GO:0019221~cytokine-mediated signaling pathway GO:0002253~activation of immune response GO:0002252~immune effector process GO:0050794~regulation of cellular process GO:0050789~regulation of biological process GO:0051716~cellular response to stimulus GO:0045087~innate immune response GO:0045785~positive regulation of cell adhesion GO:0048522~positive regulation of cellular process GO:0044763~single-organism cellular process GO:0006954~inflammatory response GO:0008150~biological_process GO:0031295~T cell costimulation GO:0031294~lymphocyte costimulation GO:0007155~cell adhesion GO:0022610~biological adhesion GO:0034341~response to interferon-
4724
107
49.18
+
2.18
1.33E-13
1696
60
17.66
+
3.40
1.88E-13
4975
110
51.79
+
2.12
1.94E-13
272
26
2.83
+
>5
2.07E-13
435
31
4.53
+
>5
4.98E-13
182
22
1.90
+
>5
5.67E-13
619
36
6.44
+
>5
6.85E-13
184
22
1.92
+
>5
7.09E-13
186
22
1.94
+
>5
8.83E-13
217
23
2.26
+
>5
1.77E-12
457
31
4.76
+
>5
1.89E-12
10450
169
108.80
+
1.55
2.63E-12
307
26
3.20
+
>5
3.52E-12
517
32
5.38
+
>5
7.53E-12
561
33
5.84
+
>5
1.08E-11
304
25
3.17
+
>5
2.56E-11
410
28
4.27
+
>5
4.98E-11
94
16
0.98
+
>5
6.16E-11
383
27
3.99
+
>5
7.40E-11
351
26
3.65
+
>5
7.72E-11
420
28
4.37
+
>5
8.94E-11
9560
156
99.53
+
1.57
2.56E-10
9962
160
103.70
+
1.54
2.72E-10
5701
112
59.35
+
1.89
5.26E-10
835
37
8.69
+
4.26
1.01E-09
338
24
3.52
+
>5
2.10E-09
4038
89
42.04
+
2.12
2.23E-09
10911
167
113.60
+
1.47
2.98E-09
416 15968 69
26 209 13
4.33 166.20 0.72
+ + +
>5 1.26 >5
3.57E-09 5.06E-09 6.03E-09
70
13
0.73
+
>5
7.21E-09
999 1003 123
39 39 15
10.40 10.44 1.28
+ + +
3.75 3.74 >5
9.96E-09 1.12E-08 4.67E-08
2
gamma GO:0071346~cellular response to interferon-gamma GO:0044699~single-organism process GO:0009607~response to biotic stimulus GO:0007166~cell surface receptor linked signal transduction GO:0060333~interferon-gammamediated signaling pathway GO:0051707~response to other organism GO:0043207~response to external biotic stimulus GO:0030217~T cell differentiation GO:0009987~cellular process GO:0031347~regulation of defense response GO:0010033~response to organic substance GO:0009966~regulation of signal transduction GO:0002443~leukocyte mediated immunity GO:0023051~regulation of signaling GO:0010646~regulation of cell communication GO:0019882~antigen processing and presentation GO:0048002~antigen processing and presentation of peptide antigen GO:0030098~lymphocyte differentiation GO:0050670~regulation of lymphocyte proliferation GO:0002449~lymphocyte mediated immunity GO:0032944~regulation of mononuclear cell proliferation GO:0002478~antigen processing and presentation of exogenous peptide antigen GO:0050900~leukocyte migration GO:0030097~hemopoiesis GO:0048534~hemopoietic or lymphoid organ development GO:0070663~regulation of leukocyte proliferation GO:0019884~antigen processing and presentation of exogenous antigen GO:0002521~leukocyte differentiation GO:0045619~regulation of lymphocyte differentiation GO:0032496~response to lipopolysaccharide GO:0051704~multi-organism process GO:0002520~immune system development GO:0006959~humoral immune response GO:0035556~intracellular signal transduction
103
14
1.07
+
>5
5.83E-08
12215
175
127.20
+
1.38
2.15E-07
677
30
7.05
+
4.26
2.60E-07
2837
67
29.54
+
2.27
4.00E-07
77
12
0.80
+
>5
4.00E-07
649
29
6.76
+
4.29
4.68E-07
649
29
6.76
+
4.29
4.68E-07
123 13503
14 184
1.28 140.60
+ +
>5 1.31
5.83E-07 2.66E-06
525
25
5.47
+
4.57
2.99E-06
2305
57
24.00
+
2.38
3.30E-06
2504
59
26.07
+
2.26
9.37E-06
154
14
1.60
+
>5
1.02E-05
2793
63
29.08
+
2.17
1.19E-05
2804
63
29.19
+
2.16
1.40E-05
224
16
2.33
+
>5
2.04E-05
194
15
2.02
+
>5
2.27E-05
198
15
2.06
+
>5
2.98E-05
168
14
1.75
+
>5
3.04E-05
114
12
1.19
+
>5
3.17E-05
169
14
1.76
+
>5
3.28E-05
171
14
1.78
+
>5
3.79E-05
237 513
16 23
2.47 5.34
+ +
>5 4.31
4.46E-05 4.76E-05
559
24
5.82
+
4.12
4.99E-05
175
14
1.82
+
>5
5.06E-05
178
14
1.85
+
>5
6.24E-05
284
17
2.96
+
>5
8.50E-05
125
12
1.30
+
>5
8.66E-05
250
16
2.60
+
>5
9.30E-05
2259
53
23.52
+
2.25
9.72E-05
588
24
6.12
+
3.92
1.29E-04
131
12
1.36
+
>5
1.44E-04
1525
41
15.88
+
2.58
1.65E-04
3
GO:0002237~response to molecule of bacterial origin GO:1902531~regulation of intracellular signal transduction GO:0071310~cellular response to organic substance GO:0009617~response to bacterium GO:0008219~cell death GO:0006915~apoptosis GO:0016265~death GO:0050671~positive regulation of lymphocyte proliferation GO:0002697~regulation of immune effector process GO:0032946~positive regulation of mononuclear cell proliferation GO:0002460~adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains GO:0012501~programmed cell death GO:1902105~regulation of leukocyte differentiation GO:0070665~positive regulation of leukocyte proliferation GO:0002250~adaptive immune response GO:0045088~regulation of innate immune response GO:0050853~B cell receptor signaling pathway GO:0009893~positive regulation of metabolic process GO:0009605~response to external stimulus GO:0070887~cellular response to chemical stimulus GO:1903706~regulation of hemopoiesis GO:0080134~regulation of response to stress GO:0050871~positive regulation of B cell activation GO:0019222~regulation of metabolic process GO:0023056~positive regulation of signaling GO:0009967~positive regulation of signal transduction GO:0019886~antigen processing and presentation of exogenous peptide antigen via MHC class II GO:0010647~positive regulation of cell communication GO:0070098~chemokine-mediated signaling pathway GO:0032101~regulation of response to external stimulus GO:0050790~regulation of catalytic activity GO:0002495~antigen processing and presentation of peptide antigen via
263
16
2.74
+
>5
1.86E-04
1541
41
16.04
+
2.56
2.20E-04
1728
44
17.99
+
2.45
2.23E-04
427 1089 1034 1094
20 33 32 33
4.45 11.34 10.76 11.39
+ + + +
4.50 2.91 2.97 2.90
2.41E-04 3.17E-04 3.23E-04 3.53E-04
115
11
1.20
+
>5
3.69E-04
278
16
2.89
+
>5
3.94E-04
116
11
1.21
+
>5
4.02E-04
118
11
1.23
+
>5
4.76E-04
1054
32
10.97
+
2.92
4.99E-04
211
14
2.20
+
>5
5.00E-04
120
11
1.25
+
>5
5.63E-04
152
12
1.58
+
>5
7.09E-04
254
15
2.64
+
>5
7.49E-04
35
7
0.36
+
>5
8.34E-04
3010
61
31.34
+
1.95
1.23E-03
1785
43
18.58
+
2.31
1.53E-03
2137
48
22.25
+
2.16
2.06E-03
277
15
2.88
+
>5
2.23E-03
1019
30
10.61
+
2.83
2.55E-03
62
8
0.65
+
>5
2.80E-03
6091
98
63.41
+
1.55
4.72E-03
1352
35
14.08
+
2.49
4.97E-03
1234
33
12.85
+
2.57
5.33E-03
93
9
0.97
+
>5
5.61E-03
1360
35
14.16
+
2.47
5.68E-03
47
7
0.49
+
>5
5.91E-03
625
22
6.51
+
3.38
6.24E-03
1953
44
20.33
+
2.16
6.67E-03
95
9
0.99
+
>5
6.68E-03
4
MHC class II GO:0002274~myeloid leukocyte activation GO:0042129~regulation of T cell proliferation GO:0002504~antigen processing and presentation of peptide or polysaccharide antigen via MHC class II GO:0050864~regulation of B cell activation GO:0065009~regulation of molecular function GO:0051239~regulation of multicellular organismal process GO:0050868~negative regulation of T cell activation GO:0045580~regulation of T cell differentiation GO:0002706~regulation of lymphocyte mediated immunity GO:0002577~regulation of antigen processing and presentation GO:0001817~regulation of cytokine production GO:0051240~positive regulation of multicellular organismal process GO:0002683~negative regulation of immune system process GO:0042221~response to chemical stimulus GO:1903038~negative regulation of leukocyte cell-cell adhesion GO:0045058~T cell selection GO:0045061~thymic T cell selection GO:0007599~hemostasis GO:0050854~regulation of antigen receptor-mediated signaling pathway GO:0043368~positive T cell selection GO:0045059~positive thymic T cell selection GO:0051246~regulation of protein metabolic process GO:0034111~negative regulation of homotypic cell-cell adhesion GO:0044093~positive regulation of molecular function GO:0002377~immunoglobulin production GO:1902107~positive regulation of leukocyte differentiation GO:0060255~regulation of macromolecule metabolic process GO:0016064~immunoglobulin mediated immune response GO:0042981~regulation of apoptosis GO:0042127~regulation of cell proliferation GO:0019724~B cell mediated immunity GO:0030595~leukocyte chemotaxis GO:0043067~regulation of programmed cell death
95
9
0.99
+
>5
6.68E-03
125
10
1.30
+
>5
7.49E-03
97
9
1.01
+
>5
7.91E-03
97
9
1.01
+
>5
7.91E-03
2383
50
24.81
+
2.02
8.28E-03
2175
47
22.64
+
2.08
8.41E-03
72
8
0.75
+
>5
8.47E-03
98
9
1.02
+
>5
8.60E-03
98
9
1.02
+
>5
8.60E-03
17
5
0.18
+
>5
8.83E-03
490
19
5.10
+
3.72
9.02E-03
1204
32
12.53
+
2.55
9.13E-03
312
15
3.25
+
4.62
9.65E-03
3591
66
37.39
+
1.77
1.13E-02
77
8
0.80
+
>5
1.39E-02
34 19 508
6 5 19
0.35 0.20 5.29
+ + +
>5 >5 3.59
1.40E-02 1.51E-02 1.52E-02
35
6
0.36
+
>5
1.66E-02
20
5
0.21
+
>5
1.94E-02
9
4
0.09
+
>5
2.14E-02
2112
45
21.99
+
2.05
2.18E-02
82
8
0.85
+
>5
2.19E-02
1469
35
15.29
+
2.29
3.17E-02
40
6
0.42
+
>5
3.53E-02
118
9
1.23
+
>5
3.82E-02
5194
84
54.07
+
1.55
4.51E-02
68
7
0.71
+
>5
6.52E-02
1331
32
13.86
+
2.31
7.17E-02
1401
33
14.59
+
2.26
7.78E-02
70 98
7 8
0.73 1.02
+ +
>5 >5
7.85E-02 7.92E-02
1341
32
13.96
+
2.29
8.32E-02
5
GO:0002503~peptide antigen assembly with MHC class II protein complex GO:0002399~MHC class II protein complex assembly GO:0050857~positive regulation of antigen receptor-mediated signaling pathway GO:0002703~regulation of leukocyte mediated immunity GO:1901700~response to oxygencontaining compound GO:0051250~negative regulation of lymphocyte activation GO:0098542~defense response to other organism GO:0045621~positive regulation of lymphocyte differentiation GO:0002440~production of molecular mediator of immune response GO:0071216~cellular response to biotic stimulus GO:0031325~positive regulation of cellular metabolic process GO:0032268~regulation of cellular protein metabolic process GO:0033077~T cell differentiation in the thymus GO:0016477~cell migration GO:0002578~negative regulation of antigen processing and presentation GO:0002501~peptide antigen assembly with MHC protein complex GO:0002396~MHC protein complex assembly GO:0032729~positive regulation of interferon-gamma production GO:0010604~positive regulation of macromolecule metabolic process GO:0008284~positive regulation of cell proliferation GO:0050817~coagulation GO:0007596~blood coagulation GO:0032649~regulation of interferongamma production GO:0045954~positive regulation of natural killer cell mediated cytotoxicity GO:0051674~localization of cell GO:0048870~cell motility GO:0071222~cellular response to lipopolysaccharide GO:0010941~regulation of cell death GO:1903708~positive regulation of hemopoiesis GO:0042102~positive regulation of T cell proliferation GO:0031399~regulation of protein modification process GO:0022408~negative regulation of cell-cell adhesion GO:0046651~lymphocyte proliferation GO:0006874~cellular calcium ion homeostasis
4
3
0.04
+
>5
8.49E-02
4
3
0.04
+
>5
8.49E-02
13
4
0.14
+
>5
9.02E-02
132
9
1.37
+
>5
9.26E-02
1222
30
12.72
+
2.36
9.45E-02
103
8
1.07
+
>5
1.13E-01
338
14
3.52
+
3.98
1.15E-01
75
7
0.78
+
>5
1.22E-01
50
6
0.52
+
>5
1.24E-01
137
9
1.43
+
>5
1.24E-01
2485
48
25.87
+
1.86
1.33E-01
1916
40
19.95
+
2.01
1.38E-01
52
6
0.54
+
>5
1.54E-01
713
21
7.42
+
2.83
1.64E-01
5
3
0.05
+
>5
1.65E-01
5
3
0.05
+
>5
1.65E-01
5
3
0.05
+
>5
1.65E-01
53
6
0.55
+
>5
1.71E-01
2365
46
24.62
+
1.87
1.74E-01
776
22
8.08
+
2.72
1.84E-01
503 503
17 17
5.24 5.24
+ +
3.25 3.25
1.91E-01 1.91E-01
81
7
0.84
+
>5
1.98E-01
16
4
0.17
+
>5
2.02E-01
781 781
22 22
8.13 8.13
+ +
2.71 2.71
2.02E-01 2.02E-01
113
8
1.18
+
>5
2.17E-01
1409
32
14.67
+
2.18
2.19E-01
148
9
1.54
+
>5
2.25E-01
83
7
0.86
+
>5
2.31E-01
1283
30
13.36
+
2.25
2.34E-01
115
8
1.20
+
>5
2.45E-01
84
7
0.87
+
>5
2.49E-01
273
12
2.84
+
4.22
2.67E-01
6
GO:0043085~positive regulation of catalytic activity GO:0060326~cell chemotaxis GO:0032943~mononuclear cell proliferation GO:0006968~cellular defense response GO:0065008~regulation of biological quality GO:2000026~regulation of multicellular organismal development GO:0040011~locomotion GO:0002717~positive regulation of natural killer cell mediated immunity GO:0071219~cellular response to molecule of bacterial origin GO:0002695~negative regulation of leukocyte activation GO:0031400~negative regulation of protein modification process GO:0050878~regulation of body fluid levels GO:0002685~regulation of leukocyte migration GO:0010605~negative regulation of macromolecule metabolic process GO:0030890~positive regulation of B cell proliferation GO:0055074~calcium ion homeostasis GO:0072503~cellular divalent inorganic cation homeostasis GO:0080090~regulation of primary metabolic process GO:0070661~leukocyte proliferation GO:0050793~regulation of developmental process GO:0001819~positive regulation of cytokine production GO:0044419~interspecies interaction between organisms GO:0044403~symbiosis, encompassing mutualism through parasitism GO:0008283~cell proliferation GO:1902533~positive regulation of intracellular signal transduction GO:0042113~B cell activation GO:0098751~bone cell development GO:0051247~positive regulation of protein metabolic process GO:0001959~regulation of cytokinemediated signaling pathway GO:0002583~regulation of antigen processing and presentation of peptide antigen GO:0002708~positive regulation of lymphocyte mediated immunity GO:0042269~regulation of natural killer cell mediated cytotoxicity GO:0050866~negative regulation of cell activation GO:0002715~regulation of natural killer cell mediated immunity
1228
29
12.78
+
2.27
2.69E-01
152
9
1.58
+
>5
2.76E-01
86
7
0.90
+
>5
2.88E-01
59
6
0.61
+
>5
3.09E-01
2871
52
29.89
+
1.74
3.13E-01
1370
31
14.26
+
2.17
3.16E-01
1175
28
12.23
+
2.29
3.17E-01
18
4
0.19
+
>5
3.18E-01
120
8
1.25
+
>5
3.30E-01
121
8
1.26
+
>5
3.49E-01
426
15
4.44
+
3.38
3.65E-01
642
19
6.68
+
2.84
3.82E-01
123
8
1.28
+
>5
3.91E-01
1938
39
20.18
+
1.93
3.98E-01
38
5
0.40
+
>5
4.13E-01
286
12
2.98
+
4.03
4.14E-01
286
12
2.98
+
4.03
4.14E-01
5159
80
53.71
+
1.49
4.16E-01
92
7
0.96
+
>5
4.39E-01
1951
39
20.31
+
1.92
4.59E-01
336
13
3.50
+
3.72
4.61E-01
709
20
7.38
+
2.71
4.65E-01
709
20
7.38
+
2.71
4.65E-01
652
19
6.79
+
2.80
4.67E-01
770
21
8.02
+
2.62
4.88E-01
130 21
8 4
1.35 0.22
+ +
>5 >5
5.72E-01 5.76E-01
1217
28
12.67
+
2.21
5.78E-01
97
7
1.01
+
>5
6.08E-01
8
3
0.08
+
>5
6.58E-01
68
6
0.71
+
>5
6.70E-01
22
4
0.23
+
>5
6.88E-01
136
8
1.42
+
>5
7.79E-01
23
4
0.24
+
>5
8.15E-01
7
GO:0042098~T cell proliferation GO:0072507~divalent inorganic cation homeostasis GO:0050920~regulation of chemotaxis GO:0060759~regulation of response to cytokine stimulus GO:0043066~negative regulation of apoptotic process GO:0032270~positive regulation of cellular protein metabolic process GO:0032655~regulation of interleukin12 production GO:0014066~regulation of phosphatidylinositol 3-kinase signaling GO:0033623~regulation of integrin activation GO:0060334~regulation of interferongamma-mediated signaling pathway GO:0002381~immunoglobulin production involved in immunoglobulin mediated immune response GO:0009612~response to mechanical stimulus
44
5
0.46
+
>5
8.17E-01
308
12
3.21
+
3.74
8.27E-01
138
8
1.44
+
>5
8.60E-01
103
7
1.07
+
>5
8.79E-01
804
21
8.37
+
2.51
8.87E-01
1119
26
11.65
+
2.23
9.06E-01
45
5
0.47
+
>5
9.07E-01
72
6
0.75
+
>5
9.12E-01
9
3
0.09
+
>5
9.30E-01
24
4
0.25
+
>5
9.58E-01
24
4
0.25
+
>5
9.58E-01
180
9
1.87
+
4.80
9.84E-01
8
Table S3: Complete list of significant canonical pathways enriched in FOS. Ingenuity Pathway Analysis also identified the FOS molecules for each pathway. Ingenuity Canonical Pathways
Ratio
iCOS-iCOSL Signaling in T Helper Cells
15.40
1.43E-01
Calcium-induced T Lymphocyte Apoptosis
14.00
1.97E-01
Type I Diabetes Mellitus Signaling
12.90
1.32E-01
CD28 Signaling in T Helper Cells
12.40
1.18E-01
B Cell Development
11.70
2.78E-01
Antigen Presentation Pathway
11.00
2.38E-01
10.80
1.72E-01
10.70
1.3E-01
OX40 Signaling Pathway
10.70
1.34E-01
T Helper Cell Differentiation
10.60
1.67E-01
Crosstalk between Dendritic Cells and Natural Killer Cells
10.40
1.23E-01
PKCθ Signaling in T Lymphocytes
10.10
9.72E-02
T Cell Receptor Signaling
10.00
1.19E-01
9.78
8E-02
9.16
1.56E-01
Cdc42 Signaling
8.21
7.53E-02
Allograft Rejection Signaling
7.36
1.03E-01
Primary Immunodeficiency Signaling Altered T Cell and B Cell Signaling in Rheumatoid Arthritis
Role of NFAT in Regulation of the Immune Response Nur77 Signaling in T Lymphocytes
-log(pvalue)
Molecules CD247, HLA-DMA, HLA-DOA, IL2RG, CD3E, HLADRB1, HLA-DQB1, NFKB1, CD3D, PTPRC, CD3G, LCK, CD40, HLA-DRA, HLA-DOB, VAV1, LCP2, IL2RB CD247, CD3G, HLA-DMA, LCK, HLA-DOA, CD3E, HLA-DRA, HLA-DOB, ATP2A3, HLA-DRB1, PRKCH, HLA-DQB1, CD3D, PRKCB CD247, HLA-DMA, HLA-DOA, CD3E, PIAS1, HLADRB1, HLA-DQB1, NFKB1, CD3D, IRF1, CD3G, HLA-DRA, HLA-DOB, STAT1, TNFRSF1B, FASLG CD247, HLA-DMA, HLA-DOA, PTPN6, CD3E, HLADRB1, HLA-DQB1, NFKB1, CD3D, PTPRC, CD3G, LCK, HLA-DRA, HLA-DOB, VAV1, LCP2 PTPRC, HLA-DMA, CD19, HLA-DOA, CD40, HLADRA, HLA-DRB1, HLA-DOB, HLA-DQB1, IL7 PSMB9, HLA-DMA, HLA-DOA, HLA-DRA, HLADRB1, HLA-DOB, CD74, HLA-DPB1, TAP2, HLADPA1 BLNK, PTPRC, BTK, LCK, CD19, IL2RG, CD3E, CD40, CD8A, CD3D, TAP2 HLA-DMA, HLA-DOA, CD40, CXCL13, TNFSF13, HLA-DRA, TLR7, HLA-DOB, HLA-DRB1, HLADQB1, NFKB1, FASLG, TNFRSF17 CD247, HLA-DMA, HLA-DOA, CD3E, HLA-DRB1, HLA-DQB1, NFKB1, CD3D, HLA-DPA1, CD3G, HLA-DRA, HLA-DOB, HLA-DPB1 HLA-DMA, IL2RG, HLA-DOA, CD40, IL21R, HLADRA, IL10RA, HLA-DRB1, HLA-DOB, HLA-DQB1, TNFRSF1B, STAT1 IL15RA, IL2RG, CD40, KLRD1, KLRC4KLRK1/KLRK1, HLA-DRA, TLR7, TNFSF10, HLADRB1, TNFRSF1B, NFKB1, FASLG, IL2RB CD247, CD3G, HLA-DMA, LCK, HLA-DOA, CD3E, HLA-DRA, HLA-DOB, HLA-DRB1, VAV1, HLADQB1, NFKB1, CD3D, LCP2 BTK, PTPRC, CD247, CD3G, LCK, CD3E, RASGRP1, VAV1, NFKB1, CD8A, CD8B, CD3D, LCP2 CD247, BLNK, HLA-DMA, HLA-DOA, CD3E, HLADRB1, HLA-DQB1, NFKB1, CD3D, BTK, CD3G, LCK, HLA-DRA, HLA-DOB, IKBKAP, LCP2 CD247, CD3G, HLA-DMA, HLA-DOA, CD3E, HLADRA, HLA-DRB1, HLA-DOB, HLA-DQB1, CD3D CD247, HLA-DMA, HLA-DOA, CD3E, HLA-DRB1, HLA-DQB1, CD3D, CLIP1, HLA-DPA1, CD3G, HLADRA, HLA-DOB, VAV1, HLA-DPB1 HLA-DMA, HLA-DOA, CD40, HLA-DRA, HLA-DRB1, HLA-DOB, HLA-DQB1, HLA-DPB1, HLA-DPA1, FASLG
1
Autoimmune Thyroid Disease Signaling Communication between Innate and Adaptive Immune Cells CCR5 Signaling in Macrophages
7.2
1.29E-01
HLA-DMA, HLA-DOA, CD40, HLA-DRA, HLA-DRB1, HLA-DOB, HLA-DQB1, FASLG
6.98
8.93E-02
CCL4, CD40, TNFSF13, HLA-DRA, TLR7, HLADRB1, CCL5, CD8A, CD8B, TNFRSF17
6.93
9.28E-02
Dendritic Cell Maturation
6.76
6.16E-02
IL-4 Signaling
6.72
1.12E-01
Natural Killer Cell Signaling
6.2
8.47E-02
Phospholipase C Signaling
6.18
5.28E-02
6.07
9.38E-02
6.02
1.37E-01
5.71
1.11E-01
5.67
4E-01
5.66
5.98E-02
BTK, LCK, TNFSF10, VAV1, PRKCH, STAT1, RHOF, NFKB1, FNBP1, FASLG, PRKCB
5.12
1.03E-01
BLNK, IL2RG, IL15RA, IL21R, STAT1, IL7, IL2RB
CTLA4 Signaling in Cytotoxic T Lymphocytes Graft-versus-Host Disease Signaling Hematopoiesis from Pluripotent Stem Cells Pathogenesis of Multiple Sclerosis Tec Kinase Signaling
CD247, CD3G, CD3E, CD8A, CD3D, CD8B, IL7 CXCL9, CCL4, CXCR3, CCL5
Role of JAK1 and JAK3 in γc Cytokine Signaling Cytotoxic T Lymphocytemediated Apoptosis of Target Cells Hepatic Fibrosis / Hepatic Stellate Cell Activation Production of Nitric Oxide and Reactive Oxygen Species in Macrophages Induction of Apoptosis by HIV1
4.5
1.28E-01
CD247, CD3G, CD3E, CD3D, FASLG
4.43
5.81E-02
CXCL9, CD40, IL10RA, CXCR3, CCL5, TNFRSF1B, STAT1, NFKB1, FASLG
4.31
4.72E-02
PTPN6, PRKCH, IRF8, TNFRSF1B, STAT1, RHOF, NFKB1, FNBP1, IRF1, PRKCB
4.2
8.96E-02
Atherosclerosis Signaling
4.04
5.76E-02
B Cell Receptor Signaling
3.98
5.14E-02
3.89
5.59E-02
3.8
1.43E-01
PTPN6, PTPN2, STAT1, NFKB1
3.75
5.1E-02
CD40, MST1, PRKCH, IRF8, STAT1, NFKB1, IRF1, PRKCB
3.55
3.92E-02
PTPRC, CD247, CD3G, LCK, PTPN6, CD3E, CD40, CD72, TLR7, CD3D
3.5
6.74E-02
CD247, CD3G, CD3E, VAV1, NFKB1, CD3D
PI3K Signaling in B Lymphocytes Role of JAK1, JAK2 and TYK2 in Interferon Signaling IL-12 Signaling and Production in Macrophages Systemic Lupus Erythematosus Signaling Regulation of IL-2 Expression in Activated and Anergic T Lymphocytes
CD247, CD3G, CCL4, CD3E, PRKCH, CCL5, CD3D, FASLG, PRKCB HLA-DMA, HLA-DOA, IL32, HLA-DRB1, HLA-DQB1, NFKB1, CD40, HLA-DRA, HLA-DOB, LY75, IRF8, STAT1, TNFRSF1B RPS6KB1, HLA-DMA, IL2RG, PTPN6, HLA-DOA, HLA-DRA, HLA-DRB1, HLA-DOB, HLA-DQB1 CD247, LCK, PTPN6, SH2D1A, KLRD1, KLRC4KLRK1/KLRK1, VAV1, PRKCH, LCP2, PRKCB BLNK, CD247, CD3E, NFKB1, CD3D, BTK, CD3G, LCK, PLA2G2D, PRKCH, RHOF, LCP2, FNBP1, PRKCB CD247, CD3G, LCK, PTPN6, CD3E, CD8A, CD3D, CD8B, LCP2 HLA-DMA, HLA-DOA, HLA-DRA, HLA-DRB1, HLADOB, HLA-DQB1, FASLG
CXCR4, IKBKAP, TNFRSF1B, NFKB1, NAIP, FASLG PLA2G2D, SELP, CD40, CXCR4, RARRES3, ALOX5, NFKB1, SELPLG BLNK, PTPRC, BTK, RPS6KB1, CD19, PTPN6, VAV1, NFKB1, PRKCB BLNK, PTPRC, BTK, CD19, CD40, VAV1, NFKB1, PRKCB
2
Death Receptor Signaling Interferon Signaling IL-15 Signaling Fcγ Receptor-mediated Phagocytosis in Macrophages and Monocytes Eicosanoid Signaling Role of Pattern Recognition Receptors in Recognition of Bacteria and Viruses Granulocyte Adhesion and Diapedesis Erythropoietin Signaling Growth Hormone Signaling NF-κB Activation by Viruses Fc Epsilon RI Signaling Renin-Angiotensin Signaling Type II Diabetes Mellitus Signaling
3.25 3.2 3.15
7.35E-02 1.11E-01 6.94E-02
TNFSF10, TNFRSF1B, NFKB1, NAIP, FASLG PTPN2, PIAS1, STAT1, IRF1 LCK, IL2RG, IL15RA, NFKB1, IL2RB
3.12
5.66E-02
RPS6KB1, VAV1, PRKCH, FYB, LCP2, PRKCB
3.08
5.81E-02
LTA4H, PLA2G2D, RARRES3, ALOX5, PTGER4
3.05
5.5E-02
CLEC7A, TLR7, PRKCH, CCL5, NFKB1, PRKCB
3
4.4E-02
2.96
6.33E-02
CXCL9, CCL4, SELP, CXCL13, CXCR4, CCL5, TNFRSF1B, SELPLG RPS6KB1, PTPN6, PRKCH, NFKB1, PRKCB
2.9
6.41E-02
RPS6KB1, PTPN6, PRKCH, STAT1, PRKCB
2.77
6.02E-02
LCK, IKBKAP, PRKCH, NFKB1, PRKCB
2.76
5.13E-02
BTK, PLA2G2D, VAV1, PRKCH, LCP2, PRKCB
2.76
4.76E-02
PTPN6, PRKCH, CCL5, STAT1, NFKB1, PRKCB
2.62
3.51E-02
p38 MAPK Signaling
2.59
5E-02
p70S6K Signaling IL-15 Production TNFR2 Signaling
2.55 2.43 2.39
4.55E-02 9.68E-02 8.82E-02
NF-κB Signaling
2.38
3.87E-02
2.26
8.33E-02
2.22
3.7E-02
2.22
3.65E-02
2.21
5.48E-02
CD40, IKBKAP, STAT1, NFKB1
2.19
3.11E-02
RPS6KB1, CCND2, PRKCH, RHOF, NFKB1, FNBP1, PRKCB
2.18
7.14E-02
PLA2G2D, CD74, NFKB1
2.16
2.58E-02
2.15 2.11 2.07
7.5E-02 3.51E-02 5.33E-02
2.06
3.33E-02
2.02
5.33E-02
2.01
2.63E-02
4-1BB Signaling in T Lymphocytes 3-phosphoinositide Degradation Agranulocyte Adhesion and Diapedesis Activation of IRF by Cytosolic Pattern Recognition Receptors IL-8 Signaling MIF-mediated Glucocorticoid Regulation Molecular Mechanisms of Cancer IL-9 Signaling Gαq Signaling Chemokine Signaling Leukocyte Extravasation Signaling IL-3 Signaling Role of Macrophages, Fibroblasts and Endothelial Cells in
SLC27A2, ACSL5, PRKCH, TNFRSF1B, NFKB1, PRKCB RPS6KB1, PLA2G2D, MAP4K1, TNFRSF1B, STAT1, FASLG BTK, RPS6KB1, CD19, IL2RG, PRKCH, PRKCB STAT1, NFKB1, IRF1 TNFRSF1B, NFKB1, NAIP LCK, CD40, TLR7, TNFRSF1B, NFKB1, TNFRSF17, PRKCB TNFRSF9, IKBKAP, NFKB1 PTPRC, INPP4A, PTPN6, PTPN2, PPP1R16B, DUSP2 CXCL9, CCL4, SELP, CXCL13, CXCR4, CCL5, SELPLG
TCF4, CCND2, RASGRP1, PRKCH, RHOF, NFKB1, NAIP, FNBP1, FASLG, PRKCB IL2RG, STAT1, NFKB1 BTK, PRKCH, RHOF, NFKB1, FNBP1, PRKCB CCL4, CXCR4, CCL5, PRKCB BTK, CXCR4, RASGRP1, VAV1, PRKCH, SELPLG, PRKCB PTPN6, PRKCH, STAT1, PRKCB TCF4, IL32, TLR7, PRKCH, CCL5, TNFRSF1B, NFKB1, IL7, PRKCB
3
Rheumatoid Arthritis Fatty Acid Activation April Mediated Signaling Prolactin Signaling Phenylalanine Degradation IV (Mammalian, via Side Chain) Role of PKR in Interferon Induction and Antiviral Response B Cell Activating Factor Signaling TREM1 Signaling Glucocorticoid Receptor Signaling MIF Regulation of Innate Immunity Acute Myeloid Leukemia Signaling Leukotriene Biosynthesis VDR/RXR Activation iNOS Signaling D-myo-inositol (1,4,5,6)Tetrakisphosphate Biosynthesis D-myo-inositol (3,4,5,6)tetrakisphosphate Biosynthesis γ-linolenate Biosynthesis II (Animals) Mitochondrial L-carnitine Shuttle Pathway Differential Regulation of Cytokine Production in Macrophages and T Helper Cells by IL-17A and IL-17F Tryptophan Degradation X (Mammalian, via Tryptamine) Apoptosis Signaling CD27 Signaling in Lymphocytes HMGB1 Signaling Colorectal Cancer Metastasis Signaling UVB-Induced MAPK Signaling IL-2 Signaling D-myo-inositol-5phosphate Metabolism Thrombin Signaling Thrombopoietin Signaling Polyamine Regulation in
2.01 2.01 1.98
1.05E-01 6.82E-02 4.76E-02
SLC27A2, ACSL5 TNFSF13, NFKB1, TNFRSF17 PRKCH, STAT1, IRF1, PRKCB
1.95
5.13E-02
ALDH2, SLC27A2
1.95
6.12E-02
STAT1, NFKB1, IRF1
1.95
6.52E-02
IKBKAP, NFKB1, TNFRSF17
1.94
4.44E-02
1.93
2.68E-02
CD40, TLR7, NFKB1, NAIP CD247, CD3G, CD3E, TAF7, CCL5, STAT1, NFKB1, CD3D
1.92
5.77E-02
PLA2G2D, CD74, NFKB1
1.9
4.76E-02
RPS6KB1, TCF4, PIM1, NFKB1
1.89 1.89 1.84
7.69E-02 4.55E-02 5.66E-02
LTA4H, ALOX5 PRKCH, CCL5, PSMC5, PRKCB STAT1, NFKB1, IRF1
1.84
3.47E-02
PTPRC, PTPN6, PTPN2, PPP1R16B, DUSP2
1.84
3.47E-02
PTPRC, PTPN6, PTPN2, PPP1R16B, DUSP2
1.79
8.33E-02
SLC27A2, ACSL5
1.79
9.09E-02
SLC27A2, ACSL5
1.74
1.11E-01
CCL4, CCL5
1.74
6.9E-02
ALDH2, AKR1A1
1.71
4E-02
1.67
5.08E-02
IKBKAP, CD27, NFKB1
1.63
3.67E-02
1.63
2.61E-02
TNFRSF1B, RHOF, NFKB1, FNBP1 TCF4, TLR7, STAT1, RHOF, NFKB1, PTGER4, FNBP1
1.62
5.17E-02
RPS6KB1, PRKCH, PRKCB
1.62
4.92E-02
LCK, IL2RG, IL2RB
1.62
3.09E-02
PTPRC, PTPN6, PTPN2, PPP1R16B, DUSP2
1.61 1.58 1.57
2.84E-02 4.69E-02 6.67E-02
RPS6KB1, PRKCH, RHOF, NFKB1, FNBP1, PRKCB PRKCH, STAT1, PRKCB PSME1, TCF4
TNFRSF1B, NFKB1, NAIP, FASLG
4
Colon Cancer Differential Regulation of Cytokine Production in Intestinal Epithelial Cells by IL-17A and IL-17F Cholecystokinin/Gastrinmediated Signaling 3-phosphoinositide Biosynthesis Rac Signaling CXCR4 Signaling IL-17A Signaling in Gastric Cells Tetrahydrobiopterin Biosynthesis I Tetrahydrobiopterin Biosynthesis II Protein Kinase A Signaling CD40 Signaling GM-CSF Signaling JAK/Stat Signaling Role of MAPK Signaling in the Pathogenesis of Influenza Phenylethylamine Degradation I D-glucuronate Degradation I Fatty Acid β-oxidation I
1.54
8.7E-02
CCL4, CCL5
1.52
3.77E-02
PRKCH, RHOF, FNBP1, PRKCB
1.49
2.76E-02
PTPRC, PTPN6, PTPN2, PPP1R16B, DUSP2
1.48 1.48
3.12E-02 2.87E-02
RPS6KB1, CYFIP2, CYFIP1, NFKB1 CXCR4, PRKCH, RHOF, FNBP1, PRKCB
1.47
7.14E-02
CCL5, NFKB1
1.46
9.09E-02
GCH1
1.46
7.69E-02
GCH1
1.45
2.2E-02
1.43 1.43 1.36
4.23E-02 4.41E-02 4.23E-02
PTPRC, TCF4, PTPN6, PHKB, PTPN2, PRKCH, NFKB1, DUSP2, PRKCB CD40, IKBKAP, NFKB1 PIM1, STAT1, PRKCB PTPN6, PIAS1, STAT1
1.35
4.17E-02
PLA2G2D, RARRES3, CCL5
1.34
9.09E-02
ALDH2
1.34
7.14E-02
AKR1A1
1.32
4.44E-02
SLC27A2, ACSL5
5
