FoxP3 Expression in Tumor-Infiltrating Lymphocytes as Potential Predictor of Response to Immune Checkpoint Inhibitors in Patients with Advanced Melanoma and Non-Small Cell Lung Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
3. Results
3.1. Patient Characteristics
3.2. Correlation with Survival Parameters in the Malignant Melanoma Group
3.3. Correlation with Survival Parameters in the NSCLC Group
3.4. Co-Expression of FoxP3 and CD68
3.5. Correlation of IHC Expression with Clinical Parameters
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Variable | Overall N = 46 | Malignant Melanoma N = 31 | NSCLC N = 15 |
---|---|---|---|
Age (years) | |||
Median (IQR) | 68 (62, 73) | 70 (64, 76) | 65 (59, 71) |
Range | 43, 85 | 52, 85 | 43, 79 |
Sex | |||
Women | 11 (24%) | 8 (26%) | 3 (20%) |
Men | 35 (76%) | 23 (74%) | 12 (80%) |
Lymphocytes (×109/L) | |||
≤0.8 | 6 (13%) | 4 (13%) | 2 (13%) |
>0.8 | 40 (87%) | 27 (87%) | 13 (87%) |
Leukocytes (×109/L) | |||
≤10 | 37 (80%) | 28 (90%) | 9 (60%) |
>10 | 9 (20%) | 3 (9.7%) | 6 (40%) |
Neutrophils (×109/L) | |||
≤7 | 39 (85%) | 29 (94%) | 10 (67%) |
>7 | 7 (15%) | 2 (6.5%) | 5 (33%) |
Monocytes (×109/L) | |||
≤1.2 | 40 (87%) | 26 (84%) | 14 (93%) |
>1.2 | 6 (13%) | 5 (16%) | 1 (6.7%) |
LDH (μkat/L) | |||
≤3.55 (Men), 3.75 (Women) | 31 (78%) | 18 (72%) | 13 (87%) |
>3.55 (Men), 3.75 (Women) | 9 (22%) | 7 (28%) | 2 (13%) |
Missing | 6 | 6 | 0 |
CRP (mg/L) | |||
≤5 | 18 (49%) | 14 (64%) | 4 (27%) |
>5 | 19 (51%) | 8 (36%) | 11 (73%) |
Missing | 9 | 9 | 0 |
Metformin comedication | |||
Yes | 4 (8.7%) | 1 (3.2%) | 3 (20%) |
No | 42 (91.3%) | 30 (96.8%) | 12 (80%) |
PPI comedication | |||
Yes | 7 (15.2%) | 2 (6.4%) | 5 (33.3%) |
No | 39 (84.8%) | 29 (93.6%) | 10 (66.6%) |
Line of treatment | |||
1st line | 36 (78%) | 30 (97%) | 6 (40%) |
2nd line | 8 (17%) | 0 (0%) | 8 (53%) |
3rd or later line | 2 (4.4%) | 1 (3.2%) | 1 (6.7%) |
Best overall response | |||
Complete response | 10 (23%) | 9 (29%) | 1 (7.7%) |
Partial response | 14 (32%) | 8 (26%) | 6 (46%) |
Stable disease | 2 (4.5%) | 1 (3.2%) | 1 (7.7%) |
Disease progression | 18 (41%) | 13 (42%) | 5 (38%) |
Unknown | 2 | 0 | 2 |
Clinical benefit rate | 25 (56.8%) | 18 (58.1%) | 7 (54%) |
Unknown | 2 | 0 | 2 |
Survival parameters (median, 95% CI) | |||
PFS (months) | 10 (5.1, 19) | 11 (4.8, —) | 8.2 (5.1, —) |
OS (months) | 25 (18, —) | 27 (20, —) | 15 (9.3, —) |
Gene Variant | All Patients | Malignant Melanoma | NSCLC | |||
---|---|---|---|---|---|---|
BRAF | 14 | 45.2% | 14 | 53.8% | 0 | 0.0% |
NRAS | 12 | 38.7% | 12 | 46.2% | 0 | 0.0% |
TP53 | 8 | 25.8% | 5 | 19.2% | 2 | 40.0% |
KRAS | 3 | 9.7% | 1 | 3.8% | 2 | 40.0% |
ARID2 | 3 | 9.7% | 0 | 0.0% | 0 | 0.0% |
CDKN2A | 3 | 9.7% | 3 | 11.5% | 0 | 0.0% |
CTNNB1 | 2 | 6.5% | 2 | 7.7% | 0 | 0.0% |
PTEN | 2 | 6.5% | 0 | 0.0% | 2 | 40.0% |
ARID1A | 1 | 3.2% | 1 | 3.8% | 0 | 0.0% |
ATM | 1 | 3.2% | 0 | 0.0% | 1 | 20.0% |
POLE | 1 | 3.2% | 1 | 3.8% | 0 | 0.0% |
SF3B1 | 1 | 3.2% | 1 | 3.8% | 0 | 0.0% |
PFS | OS | ||||||
---|---|---|---|---|---|---|---|
Characteristic | N | HR | Median Survival | p-Value | HR | Median Survival | p-Value |
CD3 IEL | 0.202 | 0.122 | |||||
Negative | 13 | — | — | — | — | ||
Positive | 16 | 1.87 | 8.8 | 2.27 | 25 | ||
CD3 stromal | 0.667 | 0.834 | |||||
Negative | 6 | — | 9.5 | — | 47 | ||
Positive | 22 | 0.78 | 15 | 1.15 | 26 | ||
CD8 IEL | 0.484 | 0.093 | |||||
Negative | 17 | — | 11 | — | — | ||
Positive | 12 | 1.38 | 10 | 2.31 | 22 | ||
CD8 stromal | 0.811 | 0.539 | |||||
Negative | 7 | — | 11 | — | 13 | ||
Positive | 22 | 1.14 | 9.5 | 0.70 | 27 | ||
CD20 | 0.966 | 0.417 | |||||
Negative | 26 | — | 9.5 | — | 31 | ||
Positive | 4 | 0.97 | 13 | 1.68 | 25 | ||
CD68 | 0.034 | 0.968 | |||||
Negative | 26 | — | 15 | — | 27 | ||
Positive | 4 | 3.21 | 4.1 | 1.03 | 36 | ||
FoxP3 | 0.048 | 0.852 | |||||
Negative | 25 | — | 17 | — | 27 | ||
Positive | 4 | 3.04 | 4.5 | 1.15 | 33 | ||
IDO1 | 0.519 | 0.180 | |||||
Negative | 23 | — | 8.0 | — | 26 | ||
Positive | 7 | 0.70 | 15 | 0.38 | — | ||
LAG-3 | 0.606 | 0.770 | |||||
Negative | 23 | — | 11 | — | 31 | ||
Positive | 7 | 0.75 | 15 | 1.18 | 25 | ||
TGFβ IC | 0.384 | 0.366 | |||||
Negative | 16 | — | 5.5 | — | 27 | ||
Positive | 14 | 0.67 | 16 | 0.63 | — | ||
TGFβ TC | 0.916 | 0.991 | |||||
Negative | 26 | — | 11 | — | 27 | ||
Positive | 4 | 0.92 | 33 | 1.01 | 39 | ||
PD1 | 0.850 | 0.501 | |||||
Negative | 22 | — | 11 | — | 31 | ||
Positive | 8 | 1.10 | 10 | 1.44 | 25 | ||
PD-L1 CPS | 0.052 | 0.794 | |||||
<1 | 9 | — | 6.2 | — | 27 | ||
≥1 | 17 | 0.39 | 17 | 0.87 | 25 | ||
PD-L1 CPS | 0.195 | 0.529 | |||||
<10 | 19 | — | 8.0 | — | 26 | ||
≥10 | 7 | 0.45 | — | 0.67 | — | ||
PD-L1 CPS | 0.407 | 0.240 | |||||
<50 | 22 | — | 9.5 | — | 25 | ||
≥50 | 4 | 0.54 | 30 | 0.31 | — | ||
PD-L1 TPS | 0.005 | 0.060 | |||||
<1 | 18 | — | 5.5 | — | 20 | ||
≥1 | 9 | 0.20 | — | 0.32 | — | ||
PD-L1 TPS | 0.268 | 0.467 | |||||
<10 | 24 | — | 9.5 | — | 25 | ||
≥10 | 3 | 0.34 | — | 0.48 | — | ||
PD-L1 TPS | 0.268 | 0.467 | |||||
<50 | 24 | — | 9.5 | — | 25 | ||
≥50 | 3 | 0.34 | — | 0.48 | — | ||
TMB high | 0.058 | 0.923 | |||||
Negative | 9 | — | 4.4 | — | 27 | ||
Positive | 17 | 0.41 | 15 | 0.95 | 26 |
PFS | OS | ||||||
---|---|---|---|---|---|---|---|
Characteristic | N | HR | Median Survival | p-Value | HR | Median Survival | p-Value |
CD3 IEL | 0.767 | 0.980 | |||||
Negative | 7 | — | 6.1 | — | 14 | ||
Positive | 8 | 1.20 | 10 | 1.02 | 19 | ||
CD3 stromal | 0.289 | 0.258 | |||||
Negative | 4 | — | 4.9 | — | 14 | ||
Positive | 11 | 0.46 | 13 | 0.47 | 22 | ||
CD8 IEL | 0.089 | 0.122 | |||||
Negative | 9 | — | 14 | — | 19 | ||
Positive | 5 | 2.86 | 4.8 | 2.60 | 9.3 | ||
CD8 stromal | 0.131 | 0.423 | |||||
Negative | 7 | — | 22 | — | 15 | ||
Positive | 7 | 2.75 | 5.1 | 1.67 | 11 | ||
CD20 | 0.522 | 0.701 | |||||
Negative | 13 | — | 8.2 | — | 15 | ||
Positive | 2 | 1.66 | 10 | 0.67 | 17 | ||
CD68 | 0.097 | 0.182 | |||||
Negative | 14 | — | 10 | — | 17 | ||
Positive | 1 | 5.98 | 2.3 | 4.14 | 8.5 | ||
FoxP3 | 0.003 | 0.035 | |||||
Negative | 11 | — | 15 | — | 22 | ||
Positive | 4 | 8.70 | 3.4 | 3.86 | 8.3 | ||
IDO1 | 0.767 | 0.601 | |||||
Negative | 13 | — | 8.2 | — | 15 | ||
Positive | 2 | 1.27 | 10 | 1.51 | 13 | ||
LAG-3 | 0.146 | 0.293 | |||||
Negative | 11 | — | 13 | — | 19 | ||
Positive | 4 | 2.47 | 3.3 | 1.92 | 12 | ||
TGFβ IC | 0.115 | 0.066 | |||||
Negative | 13 | — | 13 | — | 19 | ||
Positive | 2 | 3.47 | 3.7 | 4.35 | 7.0 | ||
TGFβ TC * | |||||||
Negative | 15 | ||||||
Positive | 0 | ||||||
PD1 | 0.807 | 0.693 | |||||
Negative | 12 | — | 6.1 | — | 14 | ||
Positive | 3 | 1.18 | 15 | 1.31 | 22 | ||
PD-L1 CPS | 0.162 | 0.222 | |||||
<1 | 1 | — | — | — | — | ||
≥1 | 14 | 6.1 | 14 | ||||
PD-L1 CPS | 0.481 | 0.553 | |||||
<10 | 5 | — | 19 | — | 14 | ||
≥10 | 10 | 1.73 | 8.2 | 0.69 | 19 | ||
PD-L1 CPS | 0.439 | 0.437 | |||||
<50 | 9 | — | 14 | — | 19 | ||
≥50 | 6 | 1.60 | 5.5 | 1.63 | 13 | ||
PD-L1 TPS | 0.313 | 0.712 | |||||
<1 | 6 | — | 19 | — | 16 | ||
≥1 | 9 | 1.98 | 6.1 | 0.80 | 15 | ||
PD-L1 TPS | 0.313 | 0.712 | |||||
<10 | 6 | — | 19 | — | 16 | ||
≥10 | 9 | 1.98 | 6.1 | 0.80 | 15 | ||
PD-L1 TPS | 0.557 | 0.649 | |||||
<50 | 10 | — | 10 | — | 16 | ||
≥50 | 5 | 1.45 | 4.8 | 1.34 | 15 | ||
TMB high | 0.199 | 0.063 | |||||
Negative | 3 | — | 6.1 | — | 11 | ||
Positive | 2 | 0.00 | 21 | 0.00 | 23 |
CD68 Expression | ||||
---|---|---|---|---|
Negative | Positive | Total | p-Value 1 | |
FoxP3 nuclear expression | 0.004 | |||
negative | 24 (96%) | 1 (4.0%) | 25 (100%) | |
positive | 1 (25%) | 3 (75%) | 4 (100%) | |
total | 25 (86%) | 4 (14%) | 29 (100%) |
CD68 Expression | ||||
---|---|---|---|---|
Negative | Positive | Total | p-Value 1 | |
FoxP3 nuclear expression | 0.999 | |||
negative | 10 (91%) | 1 (9.1%) | 11 (100%) | |
positive | 4 (100%) | 0 (0%) | 4 (100%) | |
total | 14 (93%) | 1 (6.7%) | 15 (100%) |
PFS | OS | ||||||
---|---|---|---|---|---|---|---|
Characteristic | N | HR | Median Survival | p-Value | HR | Median Survival | p-Value |
FoxP3 + CD68 (melanoma group) | 0.025 | 0.517 | |||||
Both Negative | 24 | — | 17 | — | 27 | ||
Positive | 5 | 3.97 | 3.9 | 1.55 | 15 | ||
FoxP3 + CD68 (NSCLC group) | 0.001 | 0.020 | |||||
Both Negative | 10 | — | 19 | — | 23 | ||
Positive | 5 | 18.8 | 2.3 | 5.24 | 8.5 |
CRP | |||||
---|---|---|---|---|---|
≤5 mg/L | >5 mg/L | Missing | Total | p-Value | |
FoxP3 expression | 0.024 | ||||
Negative | 17 (47%) | 13 (36%) | 6 (17%) | 36 (100%) | |
Positive | 0 (0%) | 6 (75%) | 2 (25%) | 8 (100%) | |
Missing | 1 (50%) | 0 (0%) | 1 (50%) | 2 (100%) | |
Total | 18 (39%) | 19 (41%) | 9 (20%) | 46 (100%) |
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Grell, P.; Borilova, S.; Fabian, P.; Selingerova, I.; Novak, D.; Muller, P.; Kiss, I.; Vyzula, R. FoxP3 Expression in Tumor-Infiltrating Lymphocytes as Potential Predictor of Response to Immune Checkpoint Inhibitors in Patients with Advanced Melanoma and Non-Small Cell Lung Cancer. Cancers 2023, 15, 1901. https://doi.org/10.3390/cancers15061901
Grell P, Borilova S, Fabian P, Selingerova I, Novak D, Muller P, Kiss I, Vyzula R. FoxP3 Expression in Tumor-Infiltrating Lymphocytes as Potential Predictor of Response to Immune Checkpoint Inhibitors in Patients with Advanced Melanoma and Non-Small Cell Lung Cancer. Cancers. 2023; 15(6):1901. https://doi.org/10.3390/cancers15061901
Chicago/Turabian StyleGrell, Peter, Simona Borilova, Pavel Fabian, Iveta Selingerova, David Novak, Petr Muller, Igor Kiss, and Rostislav Vyzula. 2023. "FoxP3 Expression in Tumor-Infiltrating Lymphocytes as Potential Predictor of Response to Immune Checkpoint Inhibitors in Patients with Advanced Melanoma and Non-Small Cell Lung Cancer" Cancers 15, no. 6: 1901. https://doi.org/10.3390/cancers15061901