Circulating Interleukin-4 Is Associated with a Systemic T Cell Response against Tumor-Associated Antigens in Treatment-Naïve Patients with Resectable Non-Small-Cell Lung Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Association of the TA-Specific Response with Clinical Parameters
2.2. Association of the TA-Specific Response with Intratumor and Serum Cytokine Levels
2.3. Identification of Distinct Clusters
2.4. Modeling the Probability of Being a Responder
2.5. Multivariable Model for Being a Responder
2.6. Associations between Cytokine Levels and Risk Factors for Tumor Recurrence
2.7. Association of Cytokine Levels with RFS
3. Discussion
4. Materials and Methods
4.1. Study Approval and Patients
4.2. Patient Samples
4.3. Preparation of Serum and Tumor Samples
4.4. Surgery
4.5. Postoperative Follow-Up
4.6. Cell Purification and Culture
4.7. Antigens
4.8. IFN-γ ELISPOT Assay
4.9. Cytokine Quantification
4.10. Statistical Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Cytokine | n | Correlation Coefficients | Nonresponder (n = 14) | Responder (n = 22) | Wilcoxon Rank-Sum Test | |
---|---|---|---|---|---|---|
Rang Biserial | Spearman | Median | Median | p-Value | ||
IFN-γ, serum | 36 | −0.0584 | −0.0528 | 0.37 | 0.02 | 0.770 |
IL-10, serum | 35 | −0.1735 | −0.1486 | 2.21 | 1.62 | 0.402 |
IL-1ra, serum | 36 | 0.2890 | 0.2441 | 68.61 | 143.36 | 0.162 |
IL-4, serum | 36 | −0.4546 | −0.3841 | 3.79 | 2.68 | 0.030 |
IL-5, serum | 36 | −0.1234 | −0.1733 | 0.00 | 0.00 | 0.325 |
IL-6, serum | 35 | −0.0476 | −0.0430 | 0.21 | 0.00 | 0.818 |
IL-7, serum | 36 | −0.2760 | −0.2336 | 29.50 | 21.85 | 0.181 |
IL-8, serum | 36 | −0.2727 | −0.2308 | 6.52 | 4.78 | 0.186 |
IL-9, serum | 36 | 0.3507 | 0.2963 | 35.56 | 42.59 | 0.091 |
IL-12p70, serum | 36 | 0.0390 | 0.0507 | 0.00 | 0.00 | 0.785 |
IL-13, serum | 36 | −0.2435 | −0.2076 | 0.99 | 0.275 | 0.234 |
IL-15, serum | 35 | −0.1329 | −0.1828 | 0.00 | 0.00 | 0.307 |
IL-17A, serum | 36 | −0.3571 | −0.3019 | 21.79 | 14.96 | 0.086 |
Eotaxin, serum | 36 | −0.3961 | −0.3346 | 74.13 | 56.15 | 0.058 |
Basic FGF, serum | 36 | −0.1786 | −0.1549 | 7.38 | 3.39 | 0.374 |
G-CSF, serum | 36 | −0.4870 | −0.4192 | 82.41 | 1.64 | 0.019 |
IP10, serum | 36 | −0.2857 | −0.2413 | 439.00 | 328.28 | 0.167 |
MCP-1, serum | 36 | −0.0910 | −0.0768 | 38.38 | 39.02 | 0.664 |
MIP-1a, serum | 36 | −0.1071 | −0.0906 | 1.91 | 1.78 | 0.607 |
MIP-1b, serum | 36 | 0.2727 | 0.2304 | 56.055 | 60.155 | 0.187 |
PDGF BB, serum | 36 | 0.2987 | 0.2523 | 3386.99 | 4328.51 | 0.149 |
RANTES, serum | 36 | −0.0455 | −0.0384 | 9543.66 | 9162.47 | 0.834 |
TNF-α, serum | 36 | 0.0227 | 0.0192 | 13.805 | 14.15 | 0.923 |
Variable | Cutoff (pg/mL) | Crude Logistic Regression Model | Model Adjusted for Age | ||
---|---|---|---|---|---|
OR (95% CI) | p-Value | aOR (95% CI) | p-Value | ||
IL-4, serum | 3.09 | 11.3 (2.3–55.0) | 0.003 | 13.8 (2.3–82.1) | 0.004 |
IL-17A, serum | 21 | 4.5 (1.06–19.4) | 0.042 | 6.4 (1.2–34.0) | 0.029 |
Eotaxin, serum | 58 | 5.3 (1.14–24.5) | 0.033 | 5.9 (1.13–31.1) | 0.036 |
G_CSF, serum | 30 | 8.7 (1.6–48.5) | 0.014 | 15.8 (2.0–122.3) | 0.008 |
IL-7, serum | 27 | 2.9 (0.71–11.4) | 0.138 | 6.1 (1.03–36.1) | 0.037 |
IL-9, serum | 34.5 | 0.1 (0.012–0.6) | 0.012 | 0.08 (0.011–0.57) | 0.012 |
IL-1ra, serum | 178 | 0.24 (0.04–1.35) | 0.105 | 0.27 (0.05–1.63) | 0.154 |
IL-8, serum | 6 | 3.56 (0.86–14.63) | 0.079 | 15.0 (1.78–126.5) | 0.013 |
IP10, serum | 400 | 4.38 (1.03–18.63) | 0.046 | 3.69 (0.82–16.6) | 0.089 |
MIP-1b, serum | 58.5 | 0.23 (0.05–0.97) | 0.046 | 0.26 (0.06–1.16) | 0.077 |
PDGF BB, serum | 4100 | 0.26 (0.06–1.07) | 0.061 | 0.36 (0.08–1.67) | 0.193 |
Variable | Wald Chi-Square p-Value | Adjusted OR (95% CI) |
---|---|---|
Age [year] | 0.0335 | 1.16 (1.00–1.35) |
IL-4, serum (cutoff = 3.09 pg/mL) | 0.0468 | 23.23 (1.70–318.1) |
IL-8, serum (cutoff = 6 pg/mL) | 0.0185 | 22.50 (1.12–453.3) |
MIP-1b, serum (cutoff = 58.5 pg/mL) | 0.0422 | 0.054 (0.003–0.89) |
Variable | Log Rank | M1: Crude Cox Regression Model | M2: Age-Adjusted Cox Regression Model | M3: Cox Regression Model Including Cytokine Levels, the TA-Specific Response and Age | |||||
---|---|---|---|---|---|---|---|---|---|
Cytokine | Cytokine | Cytokine | TA-Specific Response | ||||||
p | HR (95% CI) | p | aHR (95% CI) | p | aHR (95% CI) | p | aHR (95% CI) | p | |
IL-4 | 0.097 | 2.8 (0.78–10.0) | 0.114 | 2.8 (0.78–9.9) | 0.116 | 1.4 (0.32–6.5) | 0.634 | 0.30 (0.06–1.6) | 0.154 |
IL-17A | 0.175 | 2.3 (0.66–8.1) | 0.190 | 2.2 (0.62–7.6) | 0.222 | 1.3 (0.33–5.0) | 0.724 | 0.27 (0.06–1.2) | 0.091 |
Eotaxin | 0.860 | 1.1 (0.32–4.0) | 0.861 | 1.1 (0.30–3.8) | 0.920 | 0.65 (0.17–2.6) | 0.535 | 0.21 (0.05–0.93) | 0.040 |
G CSF | 0.118 | 3.2 (0.68–15.1) | 0.142 | 3.3 (0.69–15.5) | 0.134 | 2.0 (0.38–11.0 | 0.408 | 0.33 (0.07–1.4) | 0.138 |
IL-7 | 0.482 | 2.1 (0.60–7.5) | 0.243 | 2.6 (0.71–9.2) | 0.152 | 1.8 (0.45–7.2) | 0.407 | 0.30 (0.07–1.3) | 0.098 |
IL-9 | 0.685 | 0.76 (0.20–2.9) | 0.688 | 0.89 (0.23–3.5) | 0.869 | 1.9 (0.44–8.1) | 0.398 | 0.19 (0.04–0.83) | 0.028 |
IL-1ra | 0.908 | 0.92 (0.24–3.6) | 0.908 | 0.97 (0.25–3.8) | 0.969 | 1.8 (0.41–8.2) | 0.432 | 0.20 (0.04–0.90) | 0.037 |
IL-8 | 0.106 | 2.7 (0.76–9.6) | 0.123 | 3.9 (1.05–14.5) | 0.042 | 2.2 (0.50–10.1) | 0.289 | 0.37 (0.07–1.9) | 0.227 |
IP-10 | 0.446 | 1.6 (0.46–5.8) | 0.454 | 1.2 (0.32–4.7) | 0.760 | 1.0 (0.27–3.9) | 0.971 | 0.25 (0.06-0.99) | 0.048 |
MIP 1b | 0.223 | 0.44 (0.11–1.7) | 0.234 | 0.48 (0.12–1.9) | 0.294 | 0.67 (0.16–2.8) | 0.578 | 0.27 (0.07–1.1) | 0.072 |
PDGF | 0.712 | 1.3 (0.36–4.5) | 0.715 | 1.7 (0.45–6.2) | 0.438 | 2.8 (0.70–11.0) | 0.115 | 0.18 (0.04–0.76) | 0.020 |
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Safi, S.; Yamauchi, Y.; Hoffmann, H.; Weichert, W.; Jost, P.J.; Winter, H.; Muley, T.; Beckhove, P. Circulating Interleukin-4 Is Associated with a Systemic T Cell Response against Tumor-Associated Antigens in Treatment-Naïve Patients with Resectable Non-Small-Cell Lung Cancer. Cancers 2020, 12, 3496. https://doi.org/10.3390/cancers12123496
Safi S, Yamauchi Y, Hoffmann H, Weichert W, Jost PJ, Winter H, Muley T, Beckhove P. Circulating Interleukin-4 Is Associated with a Systemic T Cell Response against Tumor-Associated Antigens in Treatment-Naïve Patients with Resectable Non-Small-Cell Lung Cancer. Cancers. 2020; 12(12):3496. https://doi.org/10.3390/cancers12123496
Chicago/Turabian StyleSafi, Seyer, Yoshikane Yamauchi, Hans Hoffmann, Wilko Weichert, Philipp J. Jost, Hauke Winter, Thomas Muley, and Philipp Beckhove. 2020. "Circulating Interleukin-4 Is Associated with a Systemic T Cell Response against Tumor-Associated Antigens in Treatment-Naïve Patients with Resectable Non-Small-Cell Lung Cancer" Cancers 12, no. 12: 3496. https://doi.org/10.3390/cancers12123496