Multi-Omics Perspective Reveals the Different Patterns of Tumor Immune Microenvironment Based on Programmed Death Ligand 1 (PD-L1) Expression and Predictor of Responses to Immune Checkpoint Blockade across Pan-Cancer
Abstract
:1. Introduction
2. Results
2.1. Prognostic Significance of TIL Z Score/PD-L1 to ICI Response Prediction and Stratification of Four TIME Subtypes across Pan-Cancer Types
2.2. The Composition and Abundance of Lymphocyte among Four Subtypes
2.3. Genomics Pattern Discrepancy in Four TIME Subtypes
2.4. Transcriptomics Pattern Discrepancy in Four TIME Subtypes
2.5. Hazard Analysis for Multiple Omics Factors across Four TIME Subtypes
2.6. Validation in GEO Dataset
3. Discussion
4. Materials and Methods
4.1. Data Collection and Preprocessing
4.2. Tumor-Infiltrating Lymphocyte Z Score
4.3. TIME Subtypes and Immune Cells Proportion
4.4. Genomic Analysis
4.5. Differential Gene Analysis and Pathway Score Analysis
4.6. Gene Set Variation Analysis (GSVA) Score of Gene Expression Signature
4.7. Survival Analysis
4.8. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ICI | Immune checkpoint inhibitors; |
TIME | Tumor immune microenvironment; |
PD-1 | Programmed death1; |
PD-L1 | Programmed death ligand 1; |
TCGA | The Cancer Genome Atlas; |
TIL | Tumor-infiltrating lymphocyte; |
TMB | Tumor mutation burden; |
IHC | Immunohistochemistry; |
THYM | Thymoma; |
UCS | Uterine carcinosarcoma; |
LUSC | Lung squamous cell carcinoma; |
LIHC | Liver hepatocellular carcinoma; |
TP53 | Tumor protein 53; |
TTN | Titin; |
LRP1B | LDL receptor related protein 1B; |
CSMD3 | CUB and Sushi Multiple Domains 3; |
BRAF | B-Raf Proto-Oncogene; |
FAT1 | FAT Atypical Cadherin 1; |
GTF2I | General Transcription Factor Iii; |
PCLO | Piccolo; |
ZFHX4 | Zinc Finger Homeobox 4; |
SPTA1 | Spectrin alpha, erythrocytic 1; |
APC | Adenomatous polyposis coli; |
KMT2D | Lysine methyltransferase 2D; |
PIK3CA | Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; |
PDCD1LG2 | Programmed Cell Death 1 Ligand 2; |
VTCN1 | V-set domain containing T cell activation inhibitor 1; |
PDCD1 | Programmed Cell Death 1; |
CTLA4 | Cytotoxic T-lymphocyte-associated protein 4; |
DEG | Different expressed gene; |
KEGG | Kyoto Encyclopedia of Genes and Genomes; |
IFNG | Interferon gamma; |
TNF | Tumor necrosis factor; |
TNFA | Tumor Necrosis Factor Alpha; |
IL6 | Interleukin 6; |
IL12 | Interleukin 12; |
IL12A | Interleukin 12A; |
IL12B | Interleukin 12B; |
IL10 | Interleukin 10; |
GZMB | Granzyme B; |
PRF1 | Perforin-1; |
KRAS | Kirsten ras; |
VEGFA | Vascular endothelial growth factor A; |
TGFB1 | Transforming growth factor beta 1; |
HRAS | HRas proto-oncogene; |
IDH1 | Isocitrate dehydrogenase (NADP(+)) 1; |
POLE | DNA polymerase epsilon; |
POLD1 | DNA polymerase delta 1; |
MUC16 | Mucin 16; |
RYR2 | Ryanodine receptor 2; |
SYNE1 | Spectrin repeat containing nuclear envelope protein 1; |
FLG | Filaggrin; |
USH2A | Usherin; |
CDKN2A | Cyclin dependent kinase inhibitor 2A; |
MB21D2 | Mab-21 domain containing 2; |
NDUFA13 | NADH:ubiquinone oxidoreductase subunit A13; |
DGCR6L | DiGeorge syndrome critical region gene 6 like; |
S100A1 | S100 calcium binding protein A1; |
IAPP | Islet amyloid polypeptide; |
SLC3A2 | Solute carrier family 3 member 2; |
KLF3 | Kruppel like factor 3; |
GNG12 | G protein subunit gamma 12; |
NRAS | NRAS proto-oncogene; |
RAB9B | RAB9B, member RAS oncogene family; |
SH3BGRL2 | SH3 domain binding glutamate rich protein like 2; |
TNP1 | Transition protein 1; |
RPL22 | Ribosomal protein L22; |
MRPL22 | Mitochondrial ribosomal protein L22; |
CBLN3 | Cerebellin 3 precursor; |
PAIP2 | Poly(A) binding protein interacting protein 2; |
SEC61B | SEC61 translocon subunit beta; |
DBI | Diazepam binding inhibitor; |
GNA11 | G protein subunit alpha 11; |
ARHGAP1 | Rho GTPase activating protein 1. |
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Cohorts | Cancer Type | Drug | No. of Patients | No. of Responders | No. of Non-Responders | AUC Value | ||||
---|---|---|---|---|---|---|---|---|---|---|
CD8A | CD8B | TIL (Z Score) | PD-L1 | PD-L1/TIL | ||||||
Hugo [28] | melanoma | anti-PD-1 (pembrolizumab and nivolumab) | 26 | 13 | 13 | 0.503 | 0.497 | 0.686 | 0.598 | 0.722 |
Riaz [31] | melanoma | anti-PD-1 (nivolumab) | 49 | 26 | 23 | 0.587 | 0.566 | 0.557 | 0.523 | 0.609 |
Miao [30] | ccRCC | anti-PD-1 (nivolumab) | 33 | 20 | 13 | 0.554 | 0.488 | 0.515 | 0.415 | 0.658 |
Snyder [29] | urothelial cancer | anti-PD-L1 (atezolizumab) | 25 | 9 | 16 | 0.646 | 0.632 | 0.611 | 0.59 | 0.611 |
Mariat- Hasan [32] | urothelial cancer | anti-PD-L1 (atezolizumab) | 298 | 68 | 230 | 0.585 | 0.578 | 0.589 | 0.564 | 0.6 |
Type I | Type II | Type III | Type IV | p Value | |
---|---|---|---|---|---|
No. | 280 | 3733 | 584 | 4037 | |
Age | 56.22 ± 15.01 | 57.86 ± 14.87 | 61.84 ± 13.70 | 58.94 ± 13.72 | 9 × 10−11 |
Gender | 0.0004998 | ||||
Male | 133 (47.50%) | 1562 (41.84%) | 303 (51.88%) | 2077 (51.45%) | |
Female | 147 (52.50%) | 2171 (58.16%) | 281 (48.12%) | 1960 (48.55%) | |
Stage | 0.0004998 | ||||
I | 40 (14.29%) | 630 (16.88%) | 157 (26.88%) | 933 (23.11%) | |
II | 36 (12.86%) | 749 (20.06%) | 122 (20.89%) | 815 (20.19%) | |
III | 41 (14.64%) | 489 (13.10%) | 107 (18.32%) | 649 (16.08%) | |
IV | 34 (12.14%) | 231 (6.19%) | 61 (10.45%) | 334 (8.27%) | |
T cells | 0.47 ± 0.18 | 0.28 ± 0.13 | 0.36 ± 0.14 | 0.36 ± 0.13 | <2.2 × 10−16 |
B cells | 0.08 ± 0.08 | 0.09 ± 0.09 | 0.10 ± 0.09 | 0.09 ± 0.10 | 0.0086 |
Macrophages | 0.31 ± 0.17 | 0.46 ± 0.17 | 0.41 ± 0.14 | 0.37 ± 0.15 | <2.2 × 10−16 |
DC cells | 0.06 ± 0.06 | 0.04 ± 0.06 | 0.05 ±0.06 | 0.05 ± 0.06 | <2.2 × 10−16 |
NK cells | 0.04 ± 0.04 | 0.04 ± 0.04 | 0.04 ± 0.03 | 0.05 ± 0.04 | <2.2 × 10−16 |
Mast cells | 0.04 ± 0.04 | 0.08 ± 0.07 | 0.05 ± 0.04 | 0.07 ± 0.07 | <2.2 × 10−16 |
Eosinophils | 0.00 ± 0.00 | 0.00 ± 0.02 | 0.00 ± 0.01 | 0.00 ± 0.01 | 4.2 × 10−11 |
Neutrophils | 0.00 ± 0.01 | 0.01 ± 0.02 | 0.01 ± 0.02 | 0.01 ± 0.02 | 2.1 × 10−13 |
TMB | 4.22 ± 13.22 | 6.76 ± 30.72 | 6.85 ± 13.61 | 3.65 ± 12.33 | 1.8 × 10−8 |
Neoantigens | 333.62 ± 1972.69 | 353.96 ± 1625.59 | 313.25 ± 677.87 | 187.79 ± 619.51 | 1.4 × 10−5 |
TP53-mut | 65 (23.21%) | 1409 (37.74%) | 286 (48.97%) | 1074 (26.60%) | <2.2 × 10−16 |
BRAF-mut | 35 (12.50%) | 151 (4.05%) | 30 (5.14%) | 297 (7.36%) | <2.2 × 10−16 |
HRAS-mut | 13 (4.64%) | 33 (0.88%) | 20 (3.42%) | 49 (1.21%) | 8.734 × 10−6 |
IDH1-mut | 6 (2.14%) | 346 (9.27%) | 11 (1.88%) | 85 (2.11%) | <2.2 × 10−16 |
POLE-mut | 4 (1.43%) | 120 (3.21%) | 27 (4.62%) | 92 (2.28%) | <2.2 × 10−16 |
POLD1-mut | 5 (1.79%) | 65 (1.74%) | 6 (1.03%) | 38 (0.94%) | <2.2 × 10−16 |
PDCD1LG2 CNA | <2.2 × 10−16 | ||||
Amplification | 28 (10.00%) | 114 (3.05%) | 85 (14.55%) | 88 (2.18%) | |
Deletion | 1 (0.36%) | 166 (4.45%) | 13 (2.23%) | 101 (2.50%) | |
PD-L1 CNA | <2.2 × 10−16 | ||||
Amplification | 28 (10.00%) | 114 (3.05%) | 84 (14.38%) | 87 (2.16%) | |
Deletion | 1 (0.36%) | 166 (4.45%) | 13 (2.23%) | 100 (2.48%) | |
PDCD1 CNA | 8.064 × 10−5 | ||||
Amplification | 0 (0.00%) | 101 (2.71%) | 9 (1.54%) | 47 (1.16%) | |
Deletion | 34 (12.14%) | 382 (10.23%) | 89 (15.24%) | 294 (7.28%) | |
CTLA4 CNA | 0.001178 | ||||
Amplification | 2 (0.71%) | 136 (3.64%) | 19 (3.25%) | 88 (2.18%) | |
Deletion | 16 (5.71%) | 149 (3.99%) | 46 (7.88%) | 125 (3.10%) | |
Immuno-activating cytokines | 2.81 ± 3.76 | 2.19 ± 3.49 | 4.52 ± 6.75 | 1.37 ± 2.37 | <2.2 × 10−16 |
Immuno-suppressive cytokines | 39.38 ± 33.96 | 39.24 ± 39.31 | 50.47±29.03 | 34.76 ± 37.71 | <2.2 × 10−16 |
Cytolytic activity | 34.68 ± 36.73 | 11.46 ± 19.96 | 47.71±72.69 | 12.15 ± 30.09 | <2.2 × 10−16 |
Variable | Univariate Prognostic Analysis | Multivariate Prognostic Analysis | ||||
---|---|---|---|---|---|---|
HR | 95% CI | p-Value | HR | 95% CI | p-Value | |
Age > 60 years (vs. < 60 years) | 1.87137 | 1.712–2.046 | < 2 × 10−16 | 1.848602 | 1.5988–2.1374 | <2 × 10−16 |
Gender, male (vs. female) | 1.14972 | 1.054–1.255 | 0.002 | 1.159753 | 1.0093–1.3326 | 0.036577 |
Stage II (vs. stage I) | 1.44218 | 1.219–1.706 | 1.89 × 10−5 | 1.326312 | 1.0929–1.6095 | 0.004236 |
Stage III (vs. stage I) | 2.27638 | 1.934–2.679 | <2 × 10−16 | 1.873979 | 1.5455–2.2723 | 1.69e-10 |
Stage IV (vs. stage I) | 4.66921 | 3.957–5.509 | <2 × 10−16 | 3.406277 | 2.7873–4.1627 | <2 × 10−16 |
PD-L1 positive (vs. negative) | 1.1452 | 0.9999–1.312 | 0.0501 | ———— | ————— | ———— |
TIL positive (vs. negative) | 0.69328 | 0.6345–0.7575 | 4 × 10−16 | 0.845795 | 0.7335–0.9752 | 0.021152 |
CD8+T high (vs. low) | 0.7363 | 0.6744–0.8039 | 8.31 × 10−12 | 0.91313 | 0.7891–1.0567 | 0.222529 |
CD4+T activated high (vs. low) | 1.1385 | 1.043–1.242 | 0.00355 | 1.071685 | 0.9069–1.2664 | 0.416427 |
Treg high (vs. low) | 0.8552 | 0.7836–0.9333 | 0.000453 | 0.9463 | 0.8254–1.0849 | 0.428814 |
Macro M2 high (vs. low) | 1.15472 | 1.058–1.26 | 0.00128 | 1.244084 | 1.0794–1.434 | 0.002581 |
Mast activated high (vs. low) | 1.56816 | 1.422–1.73 | <2 × 10−16 | 1.241577 | 1.0436–1.4771 | 0.014614 |
DC activated high (vs. low) | 1.18640 | 1.086–1.296 | 0.000148 | 1.028179 | 0.8939–1.1827 | 0.697222 |
NK activated high (vs. low) | 0.81109 | 0.7432–0.8852 | 2.66 × 10−6 | 1.272744 | 1.0986–1.4744 | 0.001312 |
B memory | 1.20193 | 1.087–1.329 | 0.000331 | 1.200665 | 1.0121–1.4244 | 0.035958 |
TMB high (vs. low) | 1.71388 | 1.559–1.884 | <2 × 10−16 | 1.231722 | 0.9973–1.5213 | 0.053035 |
Neoantigens high (vs. low) | 1.5202 | 1.361–1.698 | 1.01 × 10−13 | 1.029541 | 0.8496–1.2476 | 0.766486 |
TP53 mutation (vs. wild type) | 1.72522 | 1.58–1.884 | <2 × 10−16 | 1.321964 | 1.1383–1.5353 | 0.000255 |
BRAF mutation (vs. wild type) | 0.4703 | 0.3531–0.6263 | 2.44 × 10−7 | 0.772879 | 0.5504–1.0854 | 0.136993 |
IDH1 mutation (vs. wild type) | 0.6939 | 0.5493–0.8765 | 0.00218 | 1.211248 | 0.5724–2.5631 | 0.616285 |
POLE mutation (vs. wild type) | 0.96719 | 0.7449–1.256 | 0.802 | ———— | ————— | ———— |
POLD1 mutation (vs. wild type) | 0.7212 | 0.4474–1.163 | 0.18 | ———— | —————— | ———— |
PD-L1 amplification yes (vs. no) | 1.4735 | 1.208–1.797 | 0.000128 | 1.026873 | 0.764–1.3802 | 0.860481 |
PDCD1 deletion yes (vs. no) | 1.24219 | 1.084–1.424 | 0.00182 | 0.839484 | 0.6544–1.077 | 0.168638 |
CTLA4 deletion yes (vs. no) | 1.44534 | 1.193–1.752 | 0.000173 | 1.007358 | 0.7006–1.4484 | 0.968436 |
Immuno-activating cytokines high (vs. low) | 1.33658 | 1.224–1.46 | 1.1 × 10−10 | 0.987575 | 0.8485–1.1494 | 0.871716 |
Immuno-suppressive cytokines high (vs. low) | 1.69775 | 1.552–1.857 | <2 × 10−16 | 1.165356 | 1.0013–1.3563 | 0.048076 |
Cytolytic activity high (vs. low) | 1.1153 | 1.022–1.217 | 0.0144 | 1.018329 | 0.8541–1.2141 | 0.839546 |
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Huang, K.; Hu, M.; Chen, J.; Wei, J.; Qin, J.; Lin, S.; Du, H. Multi-Omics Perspective Reveals the Different Patterns of Tumor Immune Microenvironment Based on Programmed Death Ligand 1 (PD-L1) Expression and Predictor of Responses to Immune Checkpoint Blockade across Pan-Cancer. Int. J. Mol. Sci. 2021, 22, 5158. https://doi.org/10.3390/ijms22105158
Huang K, Hu M, Chen J, Wei J, Qin J, Lin S, Du H. Multi-Omics Perspective Reveals the Different Patterns of Tumor Immune Microenvironment Based on Programmed Death Ligand 1 (PD-L1) Expression and Predictor of Responses to Immune Checkpoint Blockade across Pan-Cancer. International Journal of Molecular Sciences. 2021; 22(10):5158. https://doi.org/10.3390/ijms22105158
Chicago/Turabian StyleHuang, Kaitang, Meiling Hu, Jiayun Chen, Jinfen Wei, Jingxin Qin, Shudai Lin, and Hongli Du. 2021. "Multi-Omics Perspective Reveals the Different Patterns of Tumor Immune Microenvironment Based on Programmed Death Ligand 1 (PD-L1) Expression and Predictor of Responses to Immune Checkpoint Blockade across Pan-Cancer" International Journal of Molecular Sciences 22, no. 10: 5158. https://doi.org/10.3390/ijms22105158