Higher CCL22+ Cell Infiltration is Associated with Poor Prognosis in Cervical Cancer Patients
Abstract
:1. Introduction
2. Results
2.1. CCL22 Was Overexpressed in Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (CESC)
2.2. The Association between the IRS of CCL22 in CC Cells, Infiltrating CCL22+ Cell and FOXP3+ Cell Counts with Clinical Characteristics
2.3. Higher Number of CCL22+ Cells Predicts Poor Prognosis of Patients with Cervical Cancer
2.4. Correlation Analysis between CCL22+ Expression and FOXP3+ Cells
2.5. Identification of CCL22 Expressing Cells in Cervical Cancer
2.6. Cervical Cancer Cells Induced CCL22 in Monocytes
3. Materials and Methods
3.1. Bioinformatics
3.2. Clinical Sample
3.3. Tissue Microarray Construction
3.4. Immunohistochemistry
3.4.1. Evaluation of CCL22+ Cells as Macrophages
3.4.2. Evaluation of CCL22+ Cells as M2-Like Macrophages
3.5. Cell Coculture
3.6. Elisa
3.7. Statistical Analysis
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Clinicopathological Characteristics | Total (%) | IRS of CCL22 in CC Cells | p | Quantity of CCL22+ (n%) | p | Quantity of FOXP3+ (n%) | p | |||
---|---|---|---|---|---|---|---|---|---|---|
Low (IRS < 4) | High (IRS ≥ 4) | Small (n ≤ 11) | Large (n > 11) | Small (n ≤ 29) | Large (n > 29) | |||||
All cases | 230 | 134 (58.3%) | 96 (41.7%) | − | 206 (89.6%) | 24 (10.4%) | − | 196 (85.2%) | 34 (14.8%) | − |
Age (year) | ||||||||||
≤50 | 132 (57.4%) | 80 (59.7%) | 52 (54.2%) | 0.403 | 114 (55.3%) | 18 (75.0%) | 0.065 | 115 (58.7%) | 17 (50.0%) | 0.345 |
>50 | 98 (42.6%) | 54 (40.3%) | 44 (45.8%) | 92 (44.7%) | 6 (25.0%) | 81 (41.3%) | 17 (50.0%) | |||
Tumor Size (cm) | ||||||||||
<2 | 2 (0.9%) | 2 (1.5%) | 0 (0%) | 0.080 | 2 (1.0%) | 0 (0%) | 0.090 | 2 (1.0%) | 0 (0%) | 0.905 |
2–4 | 120 (52.2%) | 75 (56%) | 45 (46.9%) | 103 (50.0%) | 17 (70.8%) | 102 (52%) | 18 (52.9%) | |||
>4 | 107 (46.5%) | 57 (42.5%) | 51 (53.1%) | 101 (49.0%) | 7 (29.2%) | 92 (46.9%) | 16 (47.1%) | |||
PN | ||||||||||
Without lymph node metastasis | 139 (60.4%) | 81 (60.4%) | 58 (60.4%) | 0.996 | 118 (57.3%) | 21 (87.5%) | 0.004 * | 122 (62.2%) | 17 (50.0%) | 0.178 |
With lymph node metastasis | 91 (39.6%) | 53 (39.6%) | 38 (39.6%) | 88 (42.7%) | 3 (12.5%) | 74 (37.8%) | 17 (50.0%) | |||
PM | ||||||||||
Without metastasis | 219 (95.2%) | 127 (94.8%) | 92 (95.8%) | 0.709 | 195 (94.7%) | 24 (100%) | 0.115 | 187 (95.4%) | 32 (94.1%) | 0.752 |
With metastasis | 11 (4.8%) | 7 (5.2%) | 4 (4.2%) | 11 (5.3%) | 0 (0%) | 9 (4.6%) | 2 (5.9%) | |||
FIGO | ||||||||||
I–IIA | 102 (44.3%) | 62 (46.3%) | 40 (41.7%) | 0.488 | 85 (41.3%) | 17 (70.8%) | 0.006 * | 87 (60.2%) | 15 (50.0%) | 0.265 |
IIB–IV | 128 (55.7%) | 55 (53.7%) | 40 (58.3%) | 121 (58.7%) | 7 (29.2%) | 109 (39.8%) | 19 (50.0%) | |||
Grade | ||||||||||
1 | 19 (8.3%) | 10 (7.8%) | 9 (9.5%) | 0.676 | 17 (8.9%) | 2 (6.1%) | 0.653 | 13 (6.7%) | 4 (12.1%) | 0.243 |
2 | 129 (56.1%) | 72 (56.3%) | 58 (60.0%) | 112 (58.9%) | 17 (51.5%) | 123 (63.1%) | 12 (36.4%) | |||
3 | 75 (32.6%) | 46 (35.9%) | 29 (30.5%) | 61 (32.1%) | 14 (42.4%) | 59 (30.3%) | 17 (51.50%) | |||
NA | 7 (3.0%) | |||||||||
Subtype | ||||||||||
Squamous carcinoma | 187 (81.3%) | 95 (70.9%) | 92 (95.8%) | 0.001 * | 171 (83.0%) | 16 (66.7%) | 0.091 | 155 (79.1%) | 32 (94.1%) | 0.038 * |
Adenocarcinoma | 43 (18.7%) | 39 (29.1%) | 4 (4.2%) | 35 (17.0%) | 8 (33.3%) | 41 (20.9%) | 2 (5.9%) | |||
Progression | ||||||||||
No | 175 (76.1%) | 99 (75.0%) | 76 (80.0%) | 0.377 | 160 (78.8%) | 15 (62.5%) | 0.072 | 149 (76.8%) | 26 (78.8%) | 0.802 |
Yes | 52 (22.6%) | 33 (25.0%) | 19 (20.0%) | 43 (21.2%) | 9 (37.5%) | 45 (23.2%) | 7 (21.2%) | |||
NA | 3 (1.3%) | |||||||||
Therapeutic Strategy | ||||||||||
Surgery | 96 (41.7%) | 59 (44.0%) | 37 (38.5%) | 0.675 | 79 (38.3%) | 17 (70.8%) | 0.007 * | 83 (42.3%) | 13 (38.2%) | 0.494 |
Preoperative chemoradiotherapy | 6 (2.6%) | 3 (2.2%) | 3 (3.1%) | 6 (2.9%) | 0 (0.0%) | 4 (2.0%) | 2 (5.9%) | |||
Chemoradiotherapy | 128 (55.7%) | 72 (53.7%) | 56 (58.3%) | 121 (58.7%) | 7 (29.2%) | 109 (55.6%) | 19 (55.9%) | |||
Survival State | ||||||||||
Alive | 198 (86.1%) | 114 (85.1%) | 84 (87.5%) | 0.600 | 183 (88.8%) | 15 (62.5%) | 0.002 * | 170 (86.7%) | 28 (82.4%) | 0.507 |
Death | 32 (13.9%) | 20 (14.9%) | 12 (12.5%) | 23 (11.2%) | 9 (37.5%) | 26 (13.3%) | 6 (17.6%) |
Group | CCL22low FOXP3low | CCL22high FOXP3low | CCL22low FOXP3high | CCL22high FOXP3high | |||||
---|---|---|---|---|---|---|---|---|---|
X2 | p-Value | X2 | p-Value | X2 | p-Value | X2 | p-Value | ||
Log Rank (Mantel–Cox) | CCL22low FOXP3low | − | − | 5.250 | 0.022 * | 0.005 | 0.946 | 8.732 | 0.003 * |
CCL22high FOXP3low | 5.250 | 0.022 * | − | − | 2.466 | 0.116 | 0.469 | 0.494 | |
CCL22low FOXP3high | 0.005 | 0.946 | 2.466 | 0.116 | − | − | 5.486 | 0.019 * | |
CCL22high FOXP3high | 8.732 | 0.003 * | 0.469 | 0.494 | 5.486 | 0.019 * | − | − |
Group | CCL22low FOXP3low | CCL22high FOXP3low | CCL22low FOXP3high | CCL22high FOXP3high | |||||
---|---|---|---|---|---|---|---|---|---|
X2 | p-Value | X2 | p-Value | X2 | p-Value | X2 | p-Value | ||
Log Rank (Mantel–Cox) | CCL22low FOXP3low | − | − | 0.519 | 0.471 | 0.490 | 0.484 | 3.320 | 0.068 |
CCL22high FOXP3low | 0.519 | 0.471 | − | − | 1.431 | 0.232 | 0.353 | 0.552 | |
CCL22low FOXP3high | 0.490 | 0.484 | 1.431 | 0.232 | − | − | 4.069 | 0.044 * | |
CCL22high FOXP3high | 3.320 | 0.068 | 0.353 | 0.552 | 4.069 | 0.044 * | − | − |
Group | CCL22low FOXP3low | CCL22high FOXP3low | CCL22low FOXP3high | CCL22high FOXP3high | ||||||
---|---|---|---|---|---|---|---|---|---|---|
X2 | p-Value | X2 | p-Value | X2 | p-Value | X2 | p-Value | |||
I–IIa | Log Rank (Mantel–Cox) | CCL22low FOXP3low | − | − | 10.547 | 0.001 * | 0.263 | 0.608 | 6.107 | 0.013 * |
CCL22high FOXP3low | 10.547 | 0.001 * | − | − | 3.122 | 0.077 | 0.010 | 0.920 | ||
CCL22low FOXP3high | 0.263 | 0.608 | 3.122 | 0.077 | − | − | 3.000 | 0.083 | ||
CCL22high FOXP3high | 6.107 | 0.013 * | 0.010 | 0.920 | 3.000 | 0.083 | − | − | ||
IIb-IV | Log Rank (Mantel–Cox) | CCL22low FOXP3low | − | − | 2.575 | 0.109 | 0.013 | 0.911 | 4.761 | 0.029 * |
CCL22high FOXP3low | 2.575 | 0.109 | − | − | 0.896 | 0.344 | 0.119 | 0.730 | ||
CCL22low FOXP3high | 0.013 | 0.911 | 0.896 | 0.344 | − | − | 1.891 | 0.169 | ||
CCL22high FOXP3high | 4.761 | 0.029 * | 0.119 | 0.730 | 1.891 | 0.169 | − | − |
Group | CCL22low FOXP3low | CCL22high FOXP3low | CCL22low FOXP3high | CCL22high FOXP3high | ||||||
---|---|---|---|---|---|---|---|---|---|---|
X2 | p-Value | X2 | p-Value | X2 | p-Value | X2 | p-Value | |||
I–IIa | Log Rank (Mantel–Cox) | CCL22low FOXP3low | − | − | 1.967 | 0.161 | 0.301 | 0.583 | 1.413 | 0.235 |
CCL22high FOXP3low | 1.967 | 0.161 | − | − | 2.888 | 0.089 | 0.029 | 0.864 | ||
CCL22low FOXP3high | 0.301 | 0.583 | 2.888 | 0.089 | − | − | 3.000 | 0.083 | ||
CCL22high FOXP3high | 1.413 | 0.235 | 0.029 | 0.864 | 3.000 | 0.083 | − | − | ||
IIb–IV | Log Rank (Mantel–Cox) | CCL22low FOXP3low | − | − | 0.603 | 0.437 | 0.004 | 0.950 | 2.515 | 0.113 |
CCL22high FOXP3low | 0.603 | 0.437 | − | − | 0.367 | 0.544 | 0.119 | 0.730 | ||
CCL22low FOXP3high | 0.004 | 0.950 | 0.367 | 0.544 | − | − | 1.160 | 0.282 | ||
CCL22high FOXP3high | 2.515 | 0.113 | 0.119 | 0.730 | 1.160 | 0.282 | − | − |
Group | CCL22low FOXP3low | CCL22high FOXP3low | CCL22low FOXP3high | CCL22high FOXP3high | ||||||
---|---|---|---|---|---|---|---|---|---|---|
X2 | p-Value | X2 | p-Value | X2 | p-Value | X2 | p-Value | |||
Squamous carcinoma | Log Rank (Mantel–Cox) | CCL22low FOXP3low | − | − | 2.133 | 0.144 | 0.011 | 0.917 | 5.399 | 0.020 |
CCL22high FOXP3low | 2.133 | 0.144 | − | − | 1.387 | 0.239 | 0.208 | 0.648 | ||
CCL22low FOXP3high | 0.011 | 0.917 | 1.387 | 0.239 | − | − | 5.139 | 0.023 * | ||
CCL22high FOXP3high | 5.399 | 0.020 * | 0.208 | 0.648 | 5.139 | 0.023 | − | − | ||
Adenocarcinoma | Log Rank (Mantel–Cox) | CCL22low FOXP3low | − | − | 1.802 | 0.179 | 1.363 | 0.243 | 4.093 | 0.043 * |
CCL22high FOXP3low | 1.802 | 0.179 | − | − | 0.264 | 0.608 | 1.824 | 0.177 | ||
CCL22low FOXP3high | 1.363 | 0.243 | 0.264 | 0.608 | − | − | 1.000 | 0.317 | ||
CCL22high FOXP3high | 4.093 | 0.043 * | 1.824 | 0.177 | 1.000 | 0.317 | − | − |
Group | CCL22low FOXP3low | CCL22high FOXP3low | CCL22low FOXP3high | CCL22high FOXP3high | ||||||
---|---|---|---|---|---|---|---|---|---|---|
X2 | p-Value | X2 | p-Value | X2 | p-Value | X2 | p-Value | |||
Squamous carcinoma | Log Rank (Mantel–Cox) | CCL22low FOXP3low | − | − | 0.011 | 0.918 | 0.739 | 0.390 | 1.327 | 0.249 |
CCL22high FOXP3low | 0.011 | 0.918 | − | − | 0.687 | 0.407 | 0.246 | 0.620 | ||
CCL22low FOXP3high | 0.739 | 0.390 | 0.687 | 0.407 | − | − | 3.438 | 0.064 | ||
CCL22high FOXP3high | 1.327 | 0.249 | 0.246 | 0.620 | 3.438 | 0.064 | − | − | ||
Adenocarcinoma | Log Rank (Mantel–Cox) | CCL22low FOXP3low | − | − | 0.770 | 0.380 | 0.796 | 0.372 | 4.175 | 0.041 * |
CCL22high FOXP3low | 0.770 | 0.380 | − | − | 0.264 | 0.608 | 1.824 | 0.177 | ||
CCL22low FOXP3high | 0.796 | 0.372 | 0.264 | 0.608 | − | − | 1.000 | 0.317 | ||
CCL22high FOXP3high | 4.175 | 0.041 * | 1.824 | 0.177 | 1.000 | 0.317 | − | − |
Clinicopathological Variables | Univariate Analysis | Multivariate Analysis | |||
---|---|---|---|---|---|
PFS | OS | PFS | OS (model 1) | OS (model 2) | |
Age (≤50 years vs. >50 years) | |||||
HR | 1.384 | 1.804 | - | - | - |
95%CI | 0.804–2.385 | 0.897–3.629 | - | - | - |
p | 0.241 | 0.098 | - | - | - |
Tumor Size (≤4 cm vs. >4 cm) | |||||
HR | 3.063 | 4.188 | 2.652 | 5.564 | 5.487 |
95%CI | 1.710–5.486 | 1.924–9.112 | 1.063–6.617 | 1.538–20.130 | 1.504–20.011 |
p | 0.001 * | 0.001 * | 0.037 * | 0.009 * | 0.010 * |
PN (Without Lymph Node Metastasis vs. Lymph Lode Metastasis) | |||||
HR | 1.851 | 2.355 | 1.555 | 2.609 | 2.547 |
95%CI | 1.065–3.218 | 1.162–4.774 | 0.756–3.200 | 1.032–6.596 | 0.988–6.562 |
p | 0.029 * | 0.017 * | 0.231 | 0.043 * | 0.053 |
PM (Without Metastasis vs. Metastasis) | |||||
HR | 1.710 | 3.303 | - | - | - |
95%CI | 0.531–5.508 | 0.999–10.924 | - | - | - |
p | 0.369 | 0.050 | - | - | - |
FIGO (I–IIa vs. IIb–IV) | |||||
HR | 2.630 | 2.913 | 1.088 | 0.584 | 0.599 |
95%CI | 1.439–4.808 | 1.340–6.332 | 0.360–3.288 | 0.134–2.536 | 0.136–2.633 |
p | 0.002 * | 0.007 * | 0.881 | 0.473 | 0.498 |
Grade (I vs. II–III) | |||||
HR | 1.672 | 1.054 | - | - | - |
95%CI | 0.520–5.375 | 0.320–3.472 | - | - | - |
p | 0.388 | 0.931 | - | - | - |
Disease Subtype (Squamous Carcinoma vs. Adenocarcinoma) | |||||
HR | 1.901 | 2.882 | 1.918 | 2.824 | 2.830 |
95%CI | 1.043–3.466 | 1.408–5.899 | 1.038–3.545 | 1.359–5.869 | 1.361–5.883 |
p | 0.036 * | 0.004 * | 0.038 * | 0.005 * | 0.005 * |
Number of CCL22+ cells (CCL22low vs. CCL22high) | |||||
HR | - | 3.41 | - | 4.985 | - |
95%CI | - | 1.567–7.419 | - | 2.206–11.266 | - |
p | - | 0.002 * | - | 0.0001 * | - |
Number of CCL22+FOXP3+ cells (CCL22lowFOXP3low vs. CCL22highFOXP3high) | |||||
HR | 2.806 | 5.355 | 3.018 | - | 5.284 |
95%CI | 0.864–9.115 | 1.580–18.154 | 0.923–9.869 | - | 1.513–18.456 |
p | 0.086 | 0.007 * | 0.068 | - | 0.009 * |
Antibody | Isotype | Clone | Dilution | Source |
---|---|---|---|---|
CCL22 | rabbit IgG | polyclonal | 1:400 in PBS a 1:400 in Dako b | Perprotech; DAKO(S322); Carpentera, CA, USA |
FoxP3 | mouse IgG | monoklonal | 1:300 in PBS a | Abcam |
CD68 | mouse IgG | polyclonal | 1:1000 in PBS a 1:1000 in Dako b | Sigma; DAKO(S322); Carpentera, CA, USA |
CD163 | mouse IgG | monoklonal | 1:800 in PBS a 1:800 in Dako b | Abcam; DAKO(S322); Carpentera, CA, USA |
Cy-3 b | goat IgG anti-rabbit | polyclonal | 1:500 b in Dako b | Dianova, Hamburg, Germany |
Cy-2 b | goat IgG anti-mouse | polyclonal | 1:100 b in Dako b | Dianova, Hamburg, Germany |
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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Wang, Q.; Schmoeckel, E.; Kost, B.P.; Kuhn, C.; Vattai, A.; Vilsmaier, T.; Mahner, S.; Mayr, D.; Jeschke, U.; Heidegger, H.H. Higher CCL22+ Cell Infiltration is Associated with Poor Prognosis in Cervical Cancer Patients. Cancers 2019, 11, 2004. https://doi.org/10.3390/cancers11122004
Wang Q, Schmoeckel E, Kost BP, Kuhn C, Vattai A, Vilsmaier T, Mahner S, Mayr D, Jeschke U, Heidegger HH. Higher CCL22+ Cell Infiltration is Associated with Poor Prognosis in Cervical Cancer Patients. Cancers. 2019; 11(12):2004. https://doi.org/10.3390/cancers11122004
Chicago/Turabian StyleWang, Qun, Elisa Schmoeckel, Bernd P. Kost, Christina Kuhn, Aurelia Vattai, Theresa Vilsmaier, Sven Mahner, Doris Mayr, Udo Jeschke, and Helene Hildegard Heidegger. 2019. "Higher CCL22+ Cell Infiltration is Associated with Poor Prognosis in Cervical Cancer Patients" Cancers 11, no. 12: 2004. https://doi.org/10.3390/cancers11122004
APA StyleWang, Q., Schmoeckel, E., Kost, B. P., Kuhn, C., Vattai, A., Vilsmaier, T., Mahner, S., Mayr, D., Jeschke, U., & Heidegger, H. H. (2019). Higher CCL22+ Cell Infiltration is Associated with Poor Prognosis in Cervical Cancer Patients. Cancers, 11(12), 2004. https://doi.org/10.3390/cancers11122004