High PD-L1/IDO-2 and PD-L2/IDO-1 Co-Expression Levels Are Associated with Worse Overall Survival in Resected Non-Small Cell Lung Cancer Patients
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patient Selection
2.2. RNA Extraction and Array Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR)
2.3. Statistical Analysis
3. Results
3.1. Patient Characteristics
3.2. PD-1, PD-L1, PD-L2, IDO-1, IDO-2 and INFγ Gene Expression and Association with Clinic-Pathological Characteristics
3.3. Prognostic Value of PD-1, PD-L1, PD-L2, IDO-1, IDO-2 and INFγ Gene Expression
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Characteristics | Patients | |
---|---|---|
N = 191 | % | |
Median Age, years (range) | 67.6 (38.7–84.3) | |
Gender | ||
Female | 54 | 28.3 |
Male | 137 | 71.7 |
Smoking History | ||
Never smokers | 16 | 8.4 |
Former smokers | 76 | 39.8 |
Current smokers | 99 | 51.8 |
Histology | ||
Invasive Adenocarcinomas | 120 | 62.8 |
Squamous cell carcinomas | 69 | 36.1 |
Adenosquamous carcinomas | 2 | 1.1 |
Grading | ||
1 | 11 | 5.8 |
2 | 99 | 51.8 |
3 | 81 | 42.4 |
pStage | ||
I | 101 | 52.9 |
II | 56 | 29.3 |
III | 34 | 17.8 |
Type of Resection | ||
Lobectomy | 183 | 95.8 |
Pneumonectomy | 4 | 2.1 |
Other | 4 | 2.1 |
Relapse | ||
No | 105 | 55.0 |
Yes | 86 | 45.0 |
Exitus | ||
Live | 95 | 49.7 |
Dead | 96 | 50.3 |
Variables | PD-1, N. (%) | PD-L1, N. (%) | PD-L2, N. (%) | IDO-1, N. (%) | IDO-2, N. (%) | INFγ, N. (%) | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Low | High | Low | High | Low | High | Low | High | Low | High | Low | High | |
N | 151 (79.1) | 40 (20.9) | 77 (40.3) | 114 (59.7) | 103 (53.4) | 88 (46.1) | 110 (57.6) | 81 (42.4) | 130 (68.1) | 61 (31.9) | 157 (82.2) | 34 (17.8) |
Age (years) | ||||||||||||
<60 | 24 (12.6) | 10 (5.2) | 11 (5.8) | 23 (12.0) | 12 (6.3) | 22 (11.5) | 16 (8.4) | 18 (9.4) | 22 (11.5) | 12 (6.3) | 25 (13.1) | 9 (4.7) |
≥60 | 127 (66.5) | 30 (15.7) | 66 (34.6) | 91 (47.6) | 91 (47.6) | 66 (34.6) | 94 (49.2) | 63 (33.0) | 108 (56.5) | 49 (25.7) | 132 (69.1) | 25 (13.1) |
p = 0.181 | p = 0.297 | p = 0.016 | p = 0.170 | p = 0.643 | p = 0.145 | |||||||
Sex | ||||||||||||
Female | 45 (23.6) | 9 (4.7) | 18 (9.4) | 36 (18.9) | 32 (16.8) | 22 (11.5) | 31 (16.2) | 23 (12.0) | 42 (22.0) | 12 (6.3) | 46 (24.1) | 8 (4.2) |
Male | 106 (55.5) | 31 (16.2) | 59 (30.9) | 78 (40.8) | 71 (37.2) | 66 (34.5) | 79 (41.4) | 58 (30.4) | 88 (46.1) | 49 (25.6) | 111 (58.1) | 26 (13.6) |
p = 0.362 | p = 0.217 | p = 0.353 | p = 0.974 | p = 0.071 | p = 0.675 | |||||||
Smoking | ||||||||||||
Never | 15 (7.9) | 1 (0.5) | 6 (3.1) | 10 (5.2) | 8 (4.2) | 8 (4.2) | 7 (3.7) | 9 (4.7) | 14 (7.3) | 2 (1.1) | 14 (7.3) | 2 (1.1) |
Current | 59 (30.9) | 17 (8.9) | 30 (15.7) | 46 (24.1) | 40 (20.9) | 36 (18.9) | 44 (23.0) | 31 (16.8) | 48 (25.1) | 28 (14.7) | 62 (32.5) | 14 (7.3) |
Former | 77 (40.3) | 22 (11.5) | 41 (21.5) | 58 (30.4) | 55 (28.8) | 44 (23.0) | 59 (30.9) | 40 (20.9) | 68 (35.6) | 31 (16.2) | 81 (42.4) | 18 (9.4) |
p = 0.388 | p = 0.975 | p = 0.882 | p = 0.502 | p = 0.162 | p = 0.920 | |||||||
Histology | ||||||||||||
Invasive Adenocarcinomas | 104 (54.4) | 16 (8.4) | 54 (28.3) | 66 (34.6) | 73 (38.2) | 47 (24.6) | 73 (38.2) | 47 (24.6) | 95 (49.7) | 25 (13.1) | 100 (52.4) | 20 (10.5) |
Squamous | 45 (23.6) | 24 (12.6) | 23 (12.0) | 46 (24.1) | 29 (15.2) | 40 (21.0) | 36 (18.9) | 33 (17.3) | 33 (17.3) | 36 (18.9) | 55 (28.8) | 14 (7.3) |
Adenosquamous | 2 (1.0) | 0 (0.0) | 0 (0.0) | 2 (1.0) | 1 (0.5) | 1 (0.5) | 1 (0.5) | 1 (0.5) | 2 (1.0) | 0 (0.0) | 2 (1.0) | 0 (0.0) |
p = 0.001 | p = 0.146 | p = 0.021 | p = 0.498 | p < 0.001 | p = 0.702 | |||||||
Grading | ||||||||||||
1 | 8 (4.2) | 3 (1.6) | 2 (1.0) | 9 (4.7) | 5 (2.6) | 6 (3.2) | 3 (1.6) | 8 (4.2) | 7 (3.7) | 4 (2.1) | 7 (3.7) | 4 (2.1) |
2 | 81 (42.4) | 18 (9.4) | 43 (22.5) | 56 (29.3) | 55 (28.8) | 44 (23.0) | 61 (31.9) | 38 (19.9) | 74 (38.7) | 25 (13.1) | 82 (43) | 17 (8.9) |
3 | 62 (32.5) | 19 (9.9) | 32 (16.8) | 49 (25.7) | 43 (22.5) | 38 (19.9) | 46 (24.1) | 35 (18.3) | 49 (25.7) | 32 (16.7) | 68 (35.6) | 13 (6.8) |
p = 0.540 | p = 0.299 | p = 0.818 | p = 0.094 | p = 0.107 | p = 0.261 | |||||||
p-Stage | ||||||||||||
I | 89 (46.6) | 12 (6.3) | 49 (25.7) | 52 (27.2) | 59 (30.9) | 42 (22.0) | 65 (34.0) | 36 (18.9) | 80 (41.9) | 21 (11.0) | 87 (45,5) | 14 (7.3) |
II | 39 (20.4) | 17 (8.9) | 18 (9.4) | 38 (19.9) | 28 (14.7) | 28 (14.7) | 31 (16.2) | 25 (13.1) | 31 (16.2) | 25 (13.1) | 45 (23.6) | 11 (5.8) |
III | 23 (12.0) | 11 (5.8) | 10 (5.2) | 24 (12.6) | 16 (8.3) | 18 (9.4) | 14 (7.3) | 20 (10.5) | 19 (9.9) | 15 (7.9) | 25 (13.1) | 9 (4.7) |
p = 0.005 | p = 0.048 | p = 0.404 | p = 0.059 | p = 0.002 | p = 0.208 |
RFS | ||||||||
---|---|---|---|---|---|---|---|---|
Univariate Analysis | Multivariate Analysis | |||||||
Variables | N. Pts at risck | HR | 95% CI | * p | HR | 95% CI | * p | |
Age | <60 (Ref) | 34 | ||||||
≥60 | 157 | 0.84 | 0.49–1.44 | 0.54 | ||||
Sex | ||||||||
F (Ref) | 54 | |||||||
M | 137 | 1.03 | 0.65–1.65 | 0.88 | ||||
Smoking | ||||||||
Never (Ref) | 16 | |||||||
Current | 76 | 2.09 | 0.82–5.30 | 0.12 | ||||
Former | 99 | 1.58 | 0.62–4.00 | 0.33 | ||||
Histology | ||||||||
Squamous (Ref) | 69 | |||||||
Adenocarcinoma | 120 | 1.62 | 1.02–2.58 | 0.03 | 2.16 | 1.30–3.60 | 0.003 | |
Adenosquamous | 2 | 1.39 | 0.18–10.25 | 0.32 | 1.36 | 0.17–10.46 | 0.76 | |
p-Stage | ||||||||
I (Ref) | 101 | |||||||
II | 56 | 1.71 | 1.05–2.79 | 0.03 | 2.13 | 1.26–3.62 | 0.005 | |
III | 34 | 2.01 | 1.17–3.41 | 0.01 | 2.13 | 1.20–3.80 | 0.01 | |
PD-1 | ||||||||
Low < 4fc (Ref) | 151 | |||||||
High ≥ 4fc | 40 | 1.17 | 0.70–21.96 | 0.52 | ||||
PD-L1 | ||||||||
Low < 4fc (Ref) | 77 | |||||||
High ≥ 4fc | 114 | 1.22 | 0.79–1.90 | 0.35 | ||||
PD-L2 | ||||||||
Low < 4fc (Ref) | 103 | |||||||
High ≥ 4fc | 88 | 1.41 | 0.92–2.15 | 0.11 | ||||
IDO-1 | ||||||||
Low < 4fc (Ref) | 110 | |||||||
High ≥ 4fc | 81 | 1.26 | 0.832–1.93 | 0.27 | ||||
IDO-2 | ||||||||
Low < 4fc (Ref) | 130 | |||||||
High ≥ 4fc | 61 | 1.33 | 0.85–2.08 | 0.20 | ||||
INFγ | ||||||||
Low < 4fc (Ref) | 157 | |||||||
High ≥ 4fc | 34 | 1.55 | 0.93–2.59 | 0.08 | ||||
PDL1/PDL2/INFγ | ||||||||
Low < 4fc (Ref) | 161 | |||||||
High ≥ 4fc | 30 | 1.90 | 1.13–3.21 | 0.01 | 1.98 | 1.06–3.71 | 0.03 |
OS | ||||||||
---|---|---|---|---|---|---|---|---|
Univariate Analysis | Multivariate Analysis | |||||||
Variables | N. Pts at risk | HR | 95% CI | * p | HR | 95% CI | * p | |
Age | ||||||||
<60 | 34 | |||||||
≥60 | 157 | 1.04 | 0.60–178 | 0.88 | ||||
Sex | ||||||||
F (Ref) | 54 | |||||||
M | 137 | 1.62 | 1.00–1.64 | 0.04 | 1.53 | 0.94 | 0.08 | |
Smoking | ||||||||
Never (Ref) | 16 | 1 | ||||||
Current | 76 | 1.81 | 0.77–4.28 | 0.17 | ||||
Former | 99 | 1.62 | 0.69–3.78 | 0.26 | ||||
Histology | ||||||||
Squamous (Ref) | 69 | |||||||
Adenocarcinoma | 120 | 1.14 | 0.75–173 | 0.53 | ||||
Adenosquamous | 2 | 0.93 | 0.12–6.85 | 0.94 | ||||
p-Stage | ||||||||
I (Ref) | 101 | 1 | ||||||
II | 56 | 1.68 | 1.07–2.64 | 0.02 | 1.65 | 1.03–2.63 | 0.03 | |
III | 34 | 1.55 | 0.90–2.66 | 0.10 | 1.46 | 0.83–2.57 | 0.18 | |
PD-1 | ||||||||
Low < 4fc (Ref) | 151 | |||||||
High ≥ 4fc | 40 | 1.26 | 0.78–2.04 | 0.29 | ||||
PD-L1 | ||||||||
Low < 4fc (Ref) | 77 | |||||||
High ≥ 4fc | 114 | 1.45 | 0.95–2.21 | 0.08 | ||||
PD-L2 | ||||||||
Low < 4fc (Ref) | 103 | |||||||
High ≥ 4fc | 88 | 1.37 | 0.91–2.04 | 0.12 | ||||
IDO-1 | ||||||||
Low < 4fc (Ref) | 110 | |||||||
High ≥ 4fc | 81 | 1.31 | 0.88–1.96 | 0.17 | ||||
IDO-2 | ||||||||
Low < 4fc (Ref) | 130 | |||||||
High ≥ 4fc | 61 | 1.47 | 0.97–2.22 | 0.06 | ||||
INFγ | ||||||||
Low < 4fc (Ref) | 157 | |||||||
High ≥ 4fc | 34 | 1.33 | 0.80–2.20 | 0.26 | ||||
PD-L1/IDO-2 | ||||||||
Low < 4fc (Ref) | 141 | |||||||
High ≥ 4fc | 50 | 1.63 | 1.06–2.51 | 0.02 | 1.98 | 1.02–3.83 | 0.04 | |
PD-L2/IDO-1 | ||||||||
Low < 4fc (Ref) | 132 | |||||||
High ≥ 4fc | 59 | 1.54 | 1.02–2.33 | 0.04 | 1.92 | 1.10–3.35 | 0.02 |
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Ludovini, V.; Bianconi, F.; Siggillino, A.; Vannucci, J.; Baglivo, S.; Berti, V.; Tofanetti, F.R.; Reda, M.S.; Bellezza, G.; Mandarano, M.; et al. High PD-L1/IDO-2 and PD-L2/IDO-1 Co-Expression Levels Are Associated with Worse Overall Survival in Resected Non-Small Cell Lung Cancer Patients. Genes 2021, 12, 273. https://doi.org/10.3390/genes12020273
Ludovini V, Bianconi F, Siggillino A, Vannucci J, Baglivo S, Berti V, Tofanetti FR, Reda MS, Bellezza G, Mandarano M, et al. High PD-L1/IDO-2 and PD-L2/IDO-1 Co-Expression Levels Are Associated with Worse Overall Survival in Resected Non-Small Cell Lung Cancer Patients. Genes. 2021; 12(2):273. https://doi.org/10.3390/genes12020273
Chicago/Turabian StyleLudovini, Vienna, Fortunato Bianconi, Annamaria Siggillino, Jacopo Vannucci, Sara Baglivo, Valeria Berti, Francesca Romana Tofanetti, Maria Sole Reda, Guido Bellezza, Martina Mandarano, and et al. 2021. "High PD-L1/IDO-2 and PD-L2/IDO-1 Co-Expression Levels Are Associated with Worse Overall Survival in Resected Non-Small Cell Lung Cancer Patients" Genes 12, no. 2: 273. https://doi.org/10.3390/genes12020273
APA StyleLudovini, V., Bianconi, F., Siggillino, A., Vannucci, J., Baglivo, S., Berti, V., Tofanetti, F. R., Reda, M. S., Bellezza, G., Mandarano, M., Belladonna, M. L., Metro, G., Chiari, R., Sidoni, A., Puma, F., Minotti, V., & Roila, F. (2021). High PD-L1/IDO-2 and PD-L2/IDO-1 Co-Expression Levels Are Associated with Worse Overall Survival in Resected Non-Small Cell Lung Cancer Patients. Genes, 12(2), 273. https://doi.org/10.3390/genes12020273