Programmed Death Ligand 1 Indicates Pre-Existing Adaptive Immune Response by Tumor-Infiltrating CD8+ T Cells in Non-Small Cell Lung Cancer
Abstract
:1. Introduction
2. Results
2.1. Correlation between PD-L1 Expression, CD8+ TIL Infiltration and Clinical Characteristics
2.2. PD-L1, IFN-γ and CD8+ TILs in NSCLC
2.3. Association of PD-L1 and CD8+ TILs with Prognosis in NSCLC Patients
2.4. RNA-Sequencing from 1018 Whole Tissue Section Tumor Samples
2.5. IFN-γ-Induced PD-L1 Upregulation is Dependent on the JAK/STAT1 Signaling Pathway
3. Discussion
4. Materials and Methods
4.1. Cell Culture and Cytokine Treatment
4.2. Patients, Cohorts and Specimens
4.3. Immunohistochemistry (IHC)
4.4. Assessment of Immunostaining Parameters
4.5. RNA Extraction and qRT-PCR Analysis
- Human PD-L1-F: 5′-TGGCATTTGCTGAACGCATTT-3′,
- Human PD-L1-R: 5′-TGCAGCCAGGTCTAATTGTTTT-3′;
- Human CD8-F: 5′-ATGGCCTTACCAGTGACCG-3′,
- Human CD8-R: 5′-AGGTTCCAGGTCCGATCCAG-3′;
- Human IFN-γ-F: 5′-TCGGTAACTGACTTGAATGTCCA-3′,
- Human IFN-γ-R: 5′-TCGCTTCCCTGTTTTAGCTGC-3′;
- Human GAPDH-F: 5′-CTCCTCCTGTTCGACAGTCAGC-3′,
- Human GAPDH-R: 5′-CCCAATACGACCAAATCCGTT-3′.
4.6. RNA-Sequencing from The Cancer Genome Atlas (TCGA)
4.7. Western Blot Analysis
4.8. Statistical Analysis
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Variables | Results |
---|---|
Gender (female/male) | 35/103 |
Median (range) age (year) | 61 (20–84) |
Tumor size (small/large) | 101/37 |
Grade (I + I-II + II /II-III + III) | 99/39 |
T stage (T1/T2/T3/T4) | 31/77/21/9 |
N stage (N0/N1/N2/Nx) | 76/21/17/24 |
M stage (M0/M1) | 134/4 |
TNM Stage (I/II/III/IV) | 65/40/29/4 |
Histology (SCC/ADC) | 70/68 |
Driver mutations (EGFR/ALK/Both) | 59/6/2 |
Treatments (CCRT with platinum/CCRT) | 90/48 |
Median (range) follow-up (months) | 53.3 (1–96) |
Status (alive/dead) | 73/65 |
PD-L1 Expression | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
Strong Positive | Weak Positive | Negative Positive | ||||||||
Subgroup | Variables | No. | % | No. | % | No. | % | No. | % | p Value α |
Overall Gender | 138 | 100 | 9 | 6.5 | 16 | 11.6 | 113 | 81.9 | 0.591 | |
F | 35 | 25.4 | 1 | 2.9 | 4 | 11.4 | 30 | 85.6 | ||
M | 103 | 74.6 | 8 | 7.8 | 12 | 11.7 | 83 | 80.6 | ||
Age | 0.839 | |||||||||
<65 | 79 | 57.2 | 6 | 7.6 | 9 | 11.4 | 64 | 81.0 | ||
≥65 | 59 | 42.8 | 3 | 5.1 | 7 | 11.9 | 49 | 83.1 | ||
Histology | 0.843 | |||||||||
SCC | 70 | 50.7 | 5 | 7.1 | 9 | 12.9 | 56 | 80.0 | ||
ADC | 68 | 49.3 | 4 | 5.9 | 7 | 10.3 | 57 | 83.8 | ||
Grades | <0.001 | |||||||||
I + I-II + II | 99 | 71.7 | 2 | 2.0 | 10 | 10.1 | 87 | 87.9 | ||
II-III + III | 39 | 28.3 | 7 | 17.9 | 6 | 15.4 | 26 | 66.7 | ||
Tumor (AJCC) | 0.146 | |||||||||
T1 | 31 | 22.5 | 1 | 3.2 | 5 | 16.1 | 25 | 80.6 | ||
T2 | 77 | 55.8 | 3 | 3.9 | 8 | 10.4 | 66 | 85.7 | ||
T3 | 21 | 15.2 | 4 | 19.0 | 1 | 4.8 | 16 | 76.2 | ||
T4 | 9 | 6.5 | 1 | 11.1 | 2 | 22.2 | 6 | 66.6 | ||
Node (AJCC) | 0.024 | |||||||||
N0 | 76 | 55.1 | 5 | 6.6 | 13 | 17.1 | 58 | 76.3 | ||
N1 | 21 | 15.2 | 4 | 19.0 | 0 | 0.0 | 17 | 81.0 | ||
N2 | 17 | 12.3 | 0 | 0.0 | 0 | 0.0 | 17 | 100.0 | ||
Nx | 24 | 17.4 | 0 | 0.0 | 3 | 12.5 | 21 | 87.5 | ||
Metastasis stage (AJCC) | 1.000 | |||||||||
M0 | 134 | 97.1 | 9 | 6.7 | 16 | 11.9 | 109 | 81.3 | ||
M1 | 4 | 2.9 | 0 | 0.0 | 0 | 0.0 | 4 | 100.0 | ||
TNM stage (AJCC) | 0.257 | |||||||||
I | 65 | 47.1 | 1 | 1.5 | 10 | 15.4 | 54 | 83.1 | ||
II | 40 | 29 | 5 | 12.5 | 4 | 10.0 | 31 | 77.5 | ||
III | 29 | 21 | 3 | 10.3 | 2 | 6.9 | 24 | 82.8 | ||
IV | 4 | 2.9 | 0 | 0.0 | 0 | 0.0 | 4 | 100.0 | ||
Tumor size | 0.370 | |||||||||
Small | 101 | 63 | 8 | 7.9 | 13 | 12.9 | 80 | 79.2 | ||
Large | 37 | 37 | 1 | 2.7 | 3 | 8.1 | 33 | 89.2 |
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Li, Y.-M.; Yu, J.-M.; Liu, Z.-Y.; Yang, H.-J.; Tang, J.; Chen, Z.-N. Programmed Death Ligand 1 Indicates Pre-Existing Adaptive Immune Response by Tumor-Infiltrating CD8+ T Cells in Non-Small Cell Lung Cancer. Int. J. Mol. Sci. 2019, 20, 5138. https://doi.org/10.3390/ijms20205138
Li Y-M, Yu J-M, Liu Z-Y, Yang H-J, Tang J, Chen Z-N. Programmed Death Ligand 1 Indicates Pre-Existing Adaptive Immune Response by Tumor-Infiltrating CD8+ T Cells in Non-Small Cell Lung Cancer. International Journal of Molecular Sciences. 2019; 20(20):5138. https://doi.org/10.3390/ijms20205138
Chicago/Turabian StyleLi, Yi-Ming, Jing-Min Yu, Zhen-Yu Liu, Hai-Jiao Yang, Juan Tang, and Zhi-Nan Chen. 2019. "Programmed Death Ligand 1 Indicates Pre-Existing Adaptive Immune Response by Tumor-Infiltrating CD8+ T Cells in Non-Small Cell Lung Cancer" International Journal of Molecular Sciences 20, no. 20: 5138. https://doi.org/10.3390/ijms20205138