Impaired Anti-Tumor T cell Response in Hepatocellular Carcinoma
Abstract
1. Introduction
2. Results
2.1. Lymphocyte Recruitment into HCC Tumor and Peritumor Site
2.2. CD56hi NK and NKT Cells Are Increased in the Tumor
2.3. Cytotoxic T Cells Are Reduced at Tumor Site, While Tregs Accumulate
2.4. Terminally Differentiated Effector T Cells Are Strongly Reduced at Tumor Site
2.5. Tumor- and Peritumor-Infiltrating T Cells Are Activated and Exhausted
3. Discussion
4. Materials and Methods
4.1. Patients
4.2. Isolation of Patients’ Peripheral Blood Mononuclear Cells (PBMC), Tumor-Infiltrating Lymphocytes (TILs) and Lymphocytes from the Peritumor Site
4.3. Flow Cytometry Analysis
4.4. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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% Within CD45+ Cells | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
Mean ± SEM | ||||||||||
PBMC Ctrl | PBMC HCC | p Value 1 | Peritumor Lymphocytes | p Value 1 | p Value 2 | TILs HCC | p Value 1 | p Value 2 | p Value 3 | |
T cells | 61.52 ± 5.16 | 37.89 ± 4.59 | 0.0071 | 49.79 ± 5.76 | 0.22 | 0.11 | 42.29 ± 7.12 | 0.09 | 0.38 | 0.51 |
NKT cells | 5.94 ± 1.64 | 10.32 ± 2.48 | 0.36 | 7.001 ± 2.45 | 0.95 | 0.47 | 6.53 ± 2.34 | 0.97 | 0.31 | 0.70 |
NK cells | 9.28 ± 1.15 | 15.72 ± 3.41 | 0.60 | 8.133 ± 1.76 | 0.68 | 0.15 | 9.80 ± 2.97 | 0.40 | 0.41 | 0.76 |
B cells | 9.76 ± 2.30 | 3.00 ± 0.58 | 0.0046 | 4.569 ± 1.72 | 0.032 | 0.67 | 1.81 ± 0.45 | 0.002 | 0.28 | 0.39 |
% Within NK Cells | ||||||||||
Mean ± SEM | ||||||||||
PBMC Ctrl | PBMC HCC | p Value 1 | Peritumor Lymphocytes | p Value 1 | p Value 2 | TILs HCC | p Value 1 | p Value 2 | p Value 3 | |
CD56hi | 7.47 ± 2.21 | 5.71 ± 1.59 | 0.47 | 18.49 ± 6.51 | 0.55 | 0.13 | 19.60 ± 6.13 | 0.07 | 0.014 | 0.78 |
CD56low | 81.15 ± 10.16 | 82.73 ± 7.43 | 0.78 | 76.45 ± 6.36 | 0.25 | 0.21 | 70.76 ± 8.65 | 0.11 | 0.10 | 1.00 |
% Within NKT Cells | ||||||||||
Mean ± SEM | ||||||||||
PBMC Ctrl | PBMC HCC | p Value 1 | Peritumor Lymphocytes | p Value 1 | p Value 2 | TILs HCC | p Value 1 | p Value 2 | p Value 3 | |
CD56hi | 8.27 ± 3.87 | 8.83 ± 6.38 | 0.35 | 10.28 ± 3.56 | 0.93 | 0.29 | 26.49 ± 9.90 | 0.11 | 0.013 | 0.14 |
CD56low | 88.49 ± 3.98 | 88.99 ± 6.42 | 0.43 | 88.15 ± 3.49 | 1.00 | 0.28 | 69.19 ± 9.61 | 0.08 | 0.003 | 0.04 |
% Within CD3+ T Cells | ||||||||||
Mean ± SEM | ||||||||||
PBMC Ctrl | PBMC HCC | p Value 1 | Peritumor Lymphocytes | p Value 1 | p Value 2 | TILs HCC | p Value 1 | p Value 2 | p Value 3 | |
CD4+ T cells | 70.29 ± 2.94 | 54.45 ± 4.97 | 0.036 | 48.13 ± 6.03 | 0.0056 | 0.74 | 48.07 ± 5.22 | 0.006 | 0.74 | 0.78 |
CD8+ T cells | 19.20 ± 2.08 | 30.97 ± 4.06 | 0.0498 | 29.514 ± 4.94 | 0.25 | 0.81 | 31.95 ± 3.65 | 0.017 | 0.48 | 0.72 |
% Within CD4+ T Cells | ||||||||||
Mean ± SEM | ||||||||||
PBMC Ctrl | PBMC HCC | p Value 1 | Peritumor Lymphocytes | p Value 1 | p Value 2 | TILs HCC | p Value 1 | p Value 2 | p Value 3 | |
Tregs | 2.28 ± 0.44 | 4.88 ± 0.97 | 0.60 | 5.32 ± 2.50 | 0.833 | 0.596 | 5.63 ± 1.59 | 0.024 | 0.840 | 0.463 |
Th1 | 0.04 ± 0.02 | 2.41 ± 1.60 | 0.12 | 4.35 ± 1.49 | 0.017 | 0.120 | 12.97 ± 7.39 | 0.024 | 0.229 | 0.779 |
T-bet+ Tregs | 0.09 ± 0.01 | 0.40 ± 0.19 | 0.88 | 0.56 ± 0.28 | 0.617 | 0.410 | 3.90 ± 1.90 | 0.2788 | 0.16 | 0.462 |
% Within CD4+ T Cells | ||||||||||
Mean ± SEM | ||||||||||
PBMC Ctrl | PBMC HCC | p Value 1 | Peritumor Lymphocytes | p Value 1 | p Value 2 | TILs HCC | p Value 1 | p Value 2 | p Value 3 | |
TN | 14.24 ± 5.80 | 18.06 ± 5.21 | 0.65 | 2.02 ± 0.66 | 0.0096 | 0.005 | 5.55 ± 3.22 | 0.030 | 0.015 | 0.69 |
TCM | 15.36 ± 6.87 | 10.24 ± 1.84 | 0.65 | 8.99 ± 3.27 | 0.46 | 0.52 | 14.69 ± 4.14 | 0.84 | 0.69 | 0.35 |
TEM | 46.54 ± 5.58 | 44.41 ± 6.02 | 0.92 | 68.80 ± 8.11 | 0.012 | 0.012 | 69.75 ± 6.98 | 0.020 | 0.007 | 0.92 |
TEFF | 26.82 ± 6.79 | 26.22 ± 6.52 | 0.60 | 11.22 ± 2.80 | 0.10 | 0.015 | 9.95 ± 1.95 | 0.09 | 0.018 | 0.97 |
% Within CD8+ T Cells | ||||||||||
Mean ± SEM | ||||||||||
PBMC Ctrl | PBMC HCC | p Value 1 | Peritumor Lymphocytes | p Value 1 | p Value 2 | TILs HCC | p Value 1 | p Value 2 | p Value 3 | |
TN | 19.90 ± 8.58 | 19.47 ± 4.99 | 0.43 | 11.56 ± 4.20 | 0.90 | 0.15 | 10.45 ± 4.61 | 0.94 | 0.06 | 0.70 |
TCM | 9.36 ± 4.39 | 4.62 ± 2.10 | 0.19 | 9.86 ± 3.99 | 0.50 | 0.05 | 14.30 ± 5.88 | 0.90 | 0.31 | 0.76 |
TEM | 40.31 ± 9.17 | 28.98 ± 4.64 | 0.32 | 51.91 ± 9.23 | 0.36 | 0.049 | 49.77 ± 8.16 | 0.36 | 0.10 | 0.85 |
TEFF | 30.43 ± 6.32 | 46.93 ± 5.90 | 0.09 | 26.68 ± 5.78 | 0.72 | 0.021 | 25.49 ± 7.26 | 0.41 | 0.023 | 0.70 |
% of CD69+ Cells | ||||||||||
Mean ± SEM | ||||||||||
PBMC Ctrl | PBMC HCC | p Value 1 | Peritumor Lymphocytes | p Value 1 | p Value 2 | TILs HCC | p Value 1 | p Value 2 | p Value 3 | |
CD4+ T cells | 8.31 ± 4.83 | 4.01 ± 0.96 | 0.64 | 15.25 ± 3.38 | 0.0057 | 0.014 | 25.26 ± 4.55 | 0.0039 | 0.010 | 0.65 |
CD8+ T cells | 6.79 ± 2.30 | 3.60 ± 0.92 | 0.38 | 14.30 ± 3.74 | 0.0006 | 0.026 | 31.87 ± 5.34 | 0.037 | 0.12 | 0.55 |
gMFI of CD69+ Cells | ||||||||||
Mean ± SEM | ||||||||||
PBMC Ctrl | PBMC HCC | p Value 1 | Peritumor Lymphocytes | p Value 1 | p Value 2 | TILs HCC | p Value 1 | p Value 2 | p Value 3 | |
CD4+ T cells | 6.31 ± 1.18 | 5.19 ± 0.65 | 0.55 | 7.20 ± 0.82 | 0.70 | 0.10 | 7.65 ± 0.90 | 0.36 | 0.054 | 0.74 |
CD8+ T cells | 5.50 ± 0.87 | 5.04 ± 0.50 | 0.59 | 7.52 ± 1.10 | 0.16 | 0.05 | 7.19 ± 0.90 | 0.18 | 0.099 | 1.00 |
% of PD1+ Cells | ||||||||||
Mean ± SEM | ||||||||||
PBMC Ctrl | PBMC HCC | p Value 1 | Peritumor Lymphocytes | p Value 1 | p Value 2 | TILs HCC | p Value 1 | p Value 2 | p Value 3 | |
CD4+ T cells | 1.12 ± 0.39 | 3.97 ± 1.95 | 0.92 | 14.98 ± 4.14 | 0.058 | 0.0045 | 18.30 ± 5.20 | 0.0033 | <0.0001 | 0.20 |
CD8+ T cells | 1.83 ± 0.67 | 5.04 ± 1.76 | 0.26 | 14.24 ± 4.82 | 0.09 | 0.017 | 17.07 ± 6.59 | 0.0004 | 0.0001 | 0.035 |
gMFI of PD1+ Cells | ||||||||||
Mean ± SEM | ||||||||||
PBMC Ctrl | PBMC HCC | p Value 1 | Peritumor Lymphocytes | p Value 1 | p Value 2 | TILs HCC | p Value 1 | p Value 2 | p Value 3 | |
CD4+ T cells | 4.58 ± 0.65 | 3.85 ± 0.51 | 0.30 | 6.12 ± 1.08 | 0.15 | 0.11 | 6.97 ± 0.67 | 0.0016 | 0.005 | 0.23 |
CD8+ T cells | 7.69 ± 3.56 | 4.28 ± 0.75 | 0.19 | 7.48 ± 1.63 | 0.21 | 0.05 | 9.97 ± 1.76 | 0.010 | 0.001 | 0.17 |
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Chaoul, N.; Mancarella, S.; Lupo, L.; Giannelli, G.; Dituri, F. Impaired Anti-Tumor T cell Response in Hepatocellular Carcinoma. Cancers 2020, 12, 627. https://doi.org/10.3390/cancers12030627
Chaoul N, Mancarella S, Lupo L, Giannelli G, Dituri F. Impaired Anti-Tumor T cell Response in Hepatocellular Carcinoma. Cancers. 2020; 12(3):627. https://doi.org/10.3390/cancers12030627
Chicago/Turabian StyleChaoul, Nada, Serena Mancarella, Luigi Lupo, Gianluigi Giannelli, and Francesco Dituri. 2020. "Impaired Anti-Tumor T cell Response in Hepatocellular Carcinoma" Cancers 12, no. 3: 627. https://doi.org/10.3390/cancers12030627
APA StyleChaoul, N., Mancarella, S., Lupo, L., Giannelli, G., & Dituri, F. (2020). Impaired Anti-Tumor T cell Response in Hepatocellular Carcinoma. Cancers, 12(3), 627. https://doi.org/10.3390/cancers12030627