Differential Expression and Clinicopathological Significance of HER2, Indoleamine 2,3-Dioxygenase and PD-L1 in Urothelial Carcinoma of the Bladder
Abstract
:1. Introduction
2. Patients and Methods
2.1. Patients and Tissue Samples
2.2. Immunohistochemical Staining Analysis
2.3. TIMER Database Analysis
2.4. Statistical Analyses
3. Results
3.1. Association of Immune Cell Infiltration with Survival and Expression of Immune Escape Genes
3.2. Association of Clinicopathological Characteristics with Expression of HER2, IDO and PD-L1
3.3. Correlation Between Expression of HER2, IDO, PD-L1, CD43 and CD8 Measured in Tumor Cells or Immune Cells
3.4. Expression of HER2 or IDO May Predict Shorter Disease-Free Survival Period in 69 Cases of pT2–pT4
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
- Siegel, R.; Naishadham, D.; Jemal, A. Cancer statistics, 2012. CA Cancer J. Clin. 2012, 62, 10–29. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kirkali, Z.; Chan, T.; Manoharan, M.; Algaba, F.; Busch, C.; Cheng, L.; Kiemeney, L.; Kriegmair, M.; Montironi, R.; Murphy, W.M.; et al. Bladder cancer: Epidemiology, staging and grading, and diagnosis. Urology 2005, 66, 4–34. [Google Scholar] [CrossRef] [PubMed]
- Porter, M.P.; Kerrigan, M.C.; Donato, B.M.; Ramsey, S.D. Patterns of use of systemic chemotherapy for Medicare beneficiaries with urothelial bladder cancer. Urol. Oncol. 2011, 29, 252–258. [Google Scholar] [CrossRef] [PubMed]
- Meeks, J.J.; Bellmunt, J.; Bochner, B.H.; Clarke, N.W.; Daneshmand, S.; Galsky, M.D.; Hahn, N.M.; Lerner, S.P.; Mason, M.; Powles, T.; et al. A systematic review of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer. Eur. Urol. 2012, 62, 523–533. [Google Scholar] [CrossRef] [PubMed]
- Helmy, K.Y.; Patel, S.A.; Nahas, G.R.; Rameshwar, P. Cancer immunotherapy: Accomplishments to date and future promise. Ther. Deliv. 2013, 4, 1307–1320. [Google Scholar] [CrossRef] [PubMed]
- Salmon, H.; Remark, R.; Gnjatic, S.; Merad, M. Host tissue determinants of tumour immunity. Nat. Rev. Cancer 2019, 19, 215–227. [Google Scholar] [CrossRef]
- Box, C.; Rogers, S.J.; Mendiola, M.; Eccles, S.A. Tumour-microenvironmental interactions: Paths to progression and targets for treatment. Semin. Cancer Biol. 2010, 20, 128–138. [Google Scholar] [CrossRef]
- Blankenstein, T.; Coulie, P.G.; Gilboa, E.; Jaffee, E.M. The determinants of tumour immunogenicity. Nat. Rev. Cancer 2012, 12, 307–313. [Google Scholar] [CrossRef]
- Kroemer, G.; Galluzzi, L.; Kepp, O.; Zitvogel, L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 2013, 31, 51–72. [Google Scholar] [CrossRef] [PubMed]
- Krysko, D.V.; Garg, A.D.; Kaczmarek, A.; Krysko, O.; Agostinis, P.; Vandenabeele, P. Immunogenic cell death and DAMPs in cancer therapy. Nat. Rev. Cancer 2012, 12, 860–875. [Google Scholar] [CrossRef]
- Huang, Y.; Zhang, S.D.; McCrudden, C.; Chan, K.W.; Lin, Y.; Kwok, H.F. The prognostic significance of PD-L1 in bladder cancer. Oncol. Rep. 2015, 33, 3075–3084. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hudolin, T.; Mengus, C.; Coulot, J.; Kastelan, Z.; El-Saleh, A.; Spagnoli, G.C. Expression of Indoleamine 2,3-Dioxygenase Gene Is a Feature of Poorly Differentiated Non-muscle-invasive Urothelial Cell Bladder Carcinomas. Anticancer Res. 2017, 37, 1375–1380. [Google Scholar] [CrossRef] [PubMed]
- Yang, C.; Zhou, Y.; Zhang, L.; Jin, C.; Li, M.; Ye, L. Expression and function analysis of indoleamine 2 and 3-dioxygenase in bladder urothelial carcinoma. Int. J. Clin. Exp. Pathol. 2015, 8, 1768–1775. [Google Scholar] [PubMed]
- Chism, D.D. Urothelial Carcinoma of the Bladder and the Rise of Immunotherapy. J. Natl. Compr. Canc. Netw. 2017, 15, 1277–1284. [Google Scholar] [CrossRef] [Green Version]
- Bellati, F.; Napoletano, C.; Ruscito, I.; Liberati, M.; Panici, P.B.; Nuti, M. Cellular adaptive immune system plays a crucial role in trastuzumab clinical efficacy. J. Clin. Oncol. 2010, 28, e369–e370. [Google Scholar] [CrossRef]
- Triulzi, T.; Forte, L.; Regondi, V.; Di Modica, M.; Ghirelli, C.; Carcangiu, M.L.; Sfondrini, L.; Balsari, A.; Tagliabue, E. HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy. Oncoimmunology 2019, 8, e1512942. [Google Scholar] [CrossRef]
- Suh, K.J.; Sung, J.H.; Kim, J.W.; Han, S.H.; Lee, H.S.; Min, A.; Kang, M.H.; Kim, J.E.; Kim, J.W.; Kim, S.H.; et al. EGFR or HER2 inhibition modulates the tumor microenvironment by suppression of PD-L1 and cytokines release. Oncotarget 2017, 8, 63901–63910. [Google Scholar] [CrossRef]
- Soliman, H.; Rawal, B.; Fulp, J.; Lee, J.H.; Lopez, A.; Bui, M.M.; Khalil, F.; Antonia, S.; Yfantis, H.G.; Lee, D.H.; et al. Analysis of indoleamine 2-3 dioxygenase (IDO1) expression in breast cancer tissue by immunohistochemistry. Cancer Immunol. Immunother. 2013, 62, 829–837. [Google Scholar] [CrossRef]
- Amin, M.; Edge, S.; Greene, F.; Byrd, D.R.; Brookland, R.K.; Washington, M.K. AJCC Cancer Staging Manual, 8th ed.; Springer: Chicago, IL, USA, 2017. [Google Scholar]
- Yeo, M.K.; Kim, J.M.; Suh, K.S.; Kim, S.H.; Lee, O.J.; Kim, K.H. Decreased Expression of the Polarity Regulatory PAR Complex Predicts Poor Prognosis of the Patients with Colorectal Adenocarcinoma. Transl. Oncol. 2018, 11, 109–115. [Google Scholar] [CrossRef]
- HercepTest™, Interpretation Manual Breast Cancer. Available online: https://www.agilent.com/cs/library/usermanuals/public/28630_herceptest_interpretation_manual-breast_ihc_row.pdf (accessed on 26 April 2020).
- PD-L1 IHC 22C3 pharmDx Interpretation Manual—Urothelial Carcinoma. Available online: https://www.agilent.com/cs/library/usermanuals/public/29276_22C3_pharmdx_uc_interpretation_manual_us.pdf (accessed on 26 April 2020).
- VENTANA PD-L1 (SP142) Assay. Available online: https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160002c.pdf (accessed on 26 April 2020).
- Allred, D.C.; Harvey, J.M.; Berardo, M.; Clark, G.M. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod. Pathol. 1998, 11, 155–168. [Google Scholar]
- Li, T.; Fan, J.; Wang, B.; Traugh, N.; Chen, Q.; Liu, J.S.; Li, B.; Liu, X.S. TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res. 2017, 77, e108–e110. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, B.; Severson, E.; Pignon, J.C.; Zhao, H.; Li, T.; Novak, J.; Jiang, P.; Shen, H.; Aster, J.C.; Rodig, S.; et al. Comprehensive analyses of tumor immunity: Implications for cancer immunotherapy. Genome Biol. 2016, 17, 174. [Google Scholar] [CrossRef] [Green Version]
- Rabinovich, G.A.; Gabrilovich, D.; Sotomayor, E.M. Immunosuppressive strategies that are mediated by tumor cells. Annu. Rev. Immunol. 2007, 25, 267–296. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Crispen, P.L.; Kusmartsev, S. Mechanisms of immune evasion in bladder cancer. Cancer Immunol. Immunother. 2020, 69, 3–14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, M.; Wang, X.; Wang, L.; Ma, X.; Gong, Z.; Zhang, S.; Li, Y. Targeting the IDO1 pathway in cancer: From bench to bedside. J. Hematol. Oncol. 2018, 11, 100. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Teng, M.W.; Galon, J.; Fridman, W.H.; Smyth, M.J. From mice to humans: Developments in cancer immunoediting. J. Clin. Investig. 2015, 125, 3338–3346. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bianchini, G.; Gianni, L. The immune system and response to HER2-targeted treatment in breast cancer. Lancet Oncol. 2014, 15, e58–e68. [Google Scholar] [CrossRef]
- Kim, R.; Emi, M.; Tanabe, K. Cancer immunoediting from immune surveillance to immune escape. Immunology 2007, 121, 1–14. [Google Scholar] [CrossRef]
- Hornyak, L.; Dobos, N.; Koncz, G.; Karanyi, Z.; Pall, D.; Szabo, Z.; Halmos, G.; Szekvolgyi, L. The Role of Indoleamine-2,3-Dioxygenase in Cancer Development, Diagnostics, and Therapy. Front. Immunol. 2018, 9, 151. [Google Scholar] [CrossRef]
- Schreiber, R.D.; Old, L.J.; Smyth, M.J. Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion. Science 2011, 331, 1565–1570. [Google Scholar] [CrossRef] [Green Version]
- Spranger, S.; Spaapen, R.M.; Zha, Y.; Williams, J.; Meng, Y.; Ha, T.T.; Gajewski, T.F. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci. Transl. Med. 2013, 5, 200ra116. [Google Scholar] [CrossRef] [Green Version]
- Wright, C.; Mellon, K.; Neal, D.E.; Johnston, P.; Corbett, I.P.; Horne, C.H. Expression of c-erbB-2 protein product in bladder cancer. Br. J. Cancer 1990, 62, 764–765. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014, 507, 315–322. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhao, J.; Xu, W.; Zhang, Z.; Song, R.; Zeng, S.; Sun, Y.; Xu, C. Prognostic role of HER2 expression in bladder cancer: A systematic review and meta-analysis. Int. Urol. Nephrol. 2015, 47, 87–94. [Google Scholar] [CrossRef] [PubMed]
- Oudard, S.; Culine, S.; Vano, Y.; Goldwasser, F.; Theodore, C.; Nguyen, T.; Voog, E.; Banu, E.; Vieillefond, A.; Priou, F.; et al. Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2. Eur. J. Cancer 2015, 51, 45–54. [Google Scholar] [CrossRef] [PubMed]
- Wulfing, C.; Machiels, J.P.; Richel, D.J.; Grimm, M.O.; Treiber, U.; De Groot, M.R.; Beuzeboc, P.; Parikh, R.; Petavy, F.; El-Hariry, I.A. A single-arm, multicenter, open-label phase 2 study of lapatinib as the second-line treatment of patients with locally advanced or metastatic transitional cell carcinoma. Cancer 2009, 115, 2881–2890. [Google Scholar] [CrossRef]
- Powles, T.; Huddart, R.A.; Elliott, T.; Sarker, S.J.; Ackerman, C.; Jones, R.; Hussain, S.; Crabb, S.; Jagdev, S.; Chester, J.; et al. Phase III, Double-Blind, Randomized Trial That Compared Maintenance Lapatinib Versus Placebo After First-Line Chemotherapy in Patients with Human Epidermal Growth Factor Receptor 1/2-Positive Metastatic Bladder Cancer. J. Clin. Oncol. 2017, 35, 48–55. [Google Scholar] [CrossRef]
- Koshkin, V.S.; O’Donnell, P.; Yu, E.Y.; Grivas, P. Systematic Review: Targeting HER2 in Bladder Cancer. Bladder Cancer 2019, 5, 1–12. [Google Scholar] [CrossRef] [Green Version]
- Triulzi, T.; De Cecco, L.; Sandri, M.; Prat, A.; Giussani, M.; Paolini, B.; Carcangiu, M.L.; Canevari, S.; Bottini, A.; Balsari, A.; et al. Whole-transcriptome analysis links trastuzumab sensitivity of breast tumors to both HER2 dependence and immune cell infiltration. Oncotarget 2015, 6, 28173–28182. [Google Scholar] [CrossRef]
- Gil Del Alcazar, C.R.; Huh, S.J.; Ekram, M.B.; Trinh, A.; Liu, L.L.; Beca, F.; Zi, X.; Kwak, M.; Bergholtz, H.; Su, Y.; et al. Immune Escape in Breast Cancer During In Situ to Invasive Carcinoma Transition. Cancer Discov. 2017, 7, 1098–1115. [Google Scholar] [CrossRef] [Green Version]
- Wu, S.; Zhang, Q.; Zhang, F.; Meng, F.; Liu, S.; Zhou, R.; Wu, Q.; Li, X.; Shen, L.; Huang, J.; et al. HER2 recruits AKT1 to disrupt STING signalling and suppress antiviral defence and antitumour immunity. Nat. Cell Biol. 2019, 21, 1027–1040. [Google Scholar] [CrossRef]
- Verma, S.; Miles, D.; Gianni, L.; Krop, I.E.; Welslau, M.; Baselga, J.; Pegram, M.; Oh, D.Y.; Dieras, V.; Guardino, E.; et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 2012, 367, 1783–1791. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ferris, R.L.; Jaffee, E.M.; Ferrone, S. Tumor antigen-targeted, monoclonal antibody-based immunotherapy: Clinical response, cellular immunity, and immunoescape. J. Clin. Oncol. 2010, 28, 4390–4399. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Brochez, L.; Chevolet, I.; Kruse, V. The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy. Eur. J. Cancer 2017, 76, 167–182. [Google Scholar] [CrossRef] [PubMed]
- Zhu, M.M.T.; Dancsok, A.R.; Nielsen, T.O. Indoleamine Dioxygenase Inhibitors: Clinical Rationale and Current Development. Curr. Oncol. Rep. 2019, 21, 2. [Google Scholar] [CrossRef]
- Mellor, A.L.; Munn, D.H. IDO expression by dendritic cells: Tolerance and tryptophan catabolism. Nat. Rev. Immunol. 2004, 4, 762–774. [Google Scholar] [CrossRef]
- El-Zaatari, M.; Chang, Y.M.; Zhang, M.; Franz, M.; Shreiner, A.; McDermott, A.J.; van der Sluijs, K.F.; Lutter, R.; Grasberger, H.; Kamada, N.; et al. Tryptophan catabolism restricts IFN-gamma-expressing neutrophils and Clostridium difficile immunopathology. J. Immunol. 2014, 193, 807–816. [Google Scholar] [CrossRef] [Green Version]
- Krishnamurthy, A.; Jimeno, A. Atezolizumab: A novel PD-L1 inhibitor in cancer therapy with a focus in bladder and non-small cell lung cancers. Drugs Today 2017, 53, 217–237. [Google Scholar] [CrossRef]
- Brody, R.; Zhang, Y.; Ballas, M.; Siddiqui, M.K.; Gupta, P.; Barker, C.; Midha, A.; Walker, J. PD-L1 expression in advanced NSCLC: Insights into risk stratification and treatment selection from a systematic literature review. Lung Cancer 2017, 112, 200–215. [Google Scholar] [CrossRef] [Green Version]
- Takada, K.; Okamoto, T.; Toyokawa, G.; Kozuma, Y.; Matsubara, T.; Haratake, N.; Akamine, T.; Takamori, S.; Katsura, M.; Shoji, F.; et al. The expression of PD-L1 protein as a prognostic factor in lung squamous cell carcinoma. Lung Cancer 2017, 104, 7–15. [Google Scholar] [CrossRef]
- Kim, H.R.; Ha, S.J.; Hong, M.H.; Heo, S.J.; Koh, Y.W.; Choi, E.C.; Kim, E.K.; Pyo, K.H.; Jung, I.; Seo, D.; et al. PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor for head and neck cancer patients. Sci. Rep. 2016, 6, 36956. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bocanegra, A.; Fernandez-Hinojal, G.; Zuazo-Ibarra, M.; Arasanz, H.; Garcia-Granda, M.J.; Hernandez, C.; Ibanez, M.; Hernandez-Marin, B.; Martinez-Aguillo, M.; Lecumberri, M.J.; et al. PD-L1 Expression in Systemic Immune Cell Populations as a Potential Predictive Biomarker of Responses to PD-L1/PD-1 Blockade Therapy in Lung Cancer. Int. J. Mol. Sci. 2019, 20, 1631. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Birtalan, E.; Danos, K.; Gurbi, B.; Brauswetter, D.; Halasz, J.; Kalocsane Piurko, V.; Acs, B.; Antal, B.; Mihalyi, R.; Pato, A.; et al. Expression of PD-L1 on Immune Cells Shows Better Prognosis in Laryngeal, Oropharygeal, and Hypopharyngeal Cancer. Appl. Immunohistochem. Mol. Morphol. 2018, 26, e79–e85. [Google Scholar] [CrossRef] [PubMed]
- Formenti, S.C.; Demaria, S. Combining radiotherapy and cancer immunotherapy: A paradigm shift. J. Natl. Cancer Inst. 2013, 105, 256–265. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McBride, W.H.; Chiang, C.S.; Olson, J.L.; Wang, C.C.; Hong, J.H.; Pajonk, F.; Dougherty, G.J.; Iwamoto, K.S.; Pervan, M.; Liao, Y.P. A sense of danger from radiation. Radiat. Res. 2004, 162, 1–19. [Google Scholar] [CrossRef]
- Haikerwal, S.J.; Hagekyriakou, J.; MacManus, M.; Martin, O.A.; Haynes, N.M. Building immunity to cancer with radiation therapy. Cancer Lett. 2015, 368, 198–208. [Google Scholar] [CrossRef]
- Wennerberg, E.; Lhuillier, C.; Vanpouille-Box, C.; Pilones, K.A.; Garcia-Martinez, E.; Rudqvist, N.P.; Formenti, S.C.; Demaria, S. Barriers to Radiation-Induced In Situ Tumor Vaccination. Front. Immunol. 2017, 8, 229. [Google Scholar] [CrossRef]
- Lyu, X.; Zhang, M.; Li, G.; Jiang, Y.; Qiao, Q. PD-1 and PD-L1 Expression Predicts Radiosensitivity and Clinical Outcomes in Head and Neck Cancer and is Associated with HPV Infection. J. Cancer 2019, 10, 937–948. [Google Scholar] [CrossRef] [Green Version]
- Duru, N.; Fan, M.; Candas, D.; Menaa, C.; Liu, H.C.; Nantajit, D.; Wen, Y.; Xiao, K.; Eldridge, A.; Chromy, B.A.; et al. HER2-associated radioresistance of breast cancer stem cells isolated from HER2-negative breast cancer cells. Clin. Cancer Res. 2012, 18, 6634–6647. [Google Scholar] [CrossRef] [Green Version]
- Cao, N.; Li, S.; Wang, Z.; Ahmed, K.M.; Degnan, M.E.; Fan, M.; Dynlacht, J.R.; Li, J.J. NF-kappaB-mediated HER2 overexpression in radiation-adaptive resistance. Radiat. Res. 2009, 171, 9–21. [Google Scholar] [CrossRef] [Green Version]
- Liu, M.; Li, Z.; Yao, W.; Zeng, X.; Wang, L.; Cheng, J.; Ma, B.; Zhang, R.; Min, W.; Wang, H. IDO inhibitor synergized with radiotherapy to delay tumor growth by reversing T cell exhaustion. Mol. Med. Rep. 2020, 21, 445–453. [Google Scholar] [CrossRef]
- Ladomersky, E.; Zhai, L.; Lenzen, A.; Lauing, K.L.; Qian, J.; Scholtens, D.M.; Gritsina, G.; Sun, X.; Liu, Y.; Yu, F.; et al. IDO1 Inhibition Synergizes with Radiation and PD-1 Blockade to Durably Increase Survival Against Advanced Glioblastoma. Clin. Cancer Res. 2018, 24, 2559–2573. [Google Scholar] [CrossRef] [Green Version]
Variable | No. | HER2 | IDO | PD-L1 (TCs) | PD-L1 (ICs) | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Low | High | p * | Low | High | p * | Low | High | p * | Low | High | p * | ||
Gender | N = 46 | N = 51 | 0.605 | N = 45 | N = 52 | 0.676 | N = 52 | N = 45 | 0.102 | N = 48 | N = 49 | 0.760 | |
Male | 78 | 38 | 40 | 37 | 41 | 45 | 33 | 38 | 40 | ||||
Female | 19 | 8 | 11 | 8 | 11 | 7 | 12 | 10 | 9 | ||||
Age (years) | 0.087 | 0.164 | 0.900 | 0.732 | |||||||||
≤65 | 36 | 13 | 23 | 20 | 16 | 19 | 17 | 17 | 19 | ||||
>65 | 61 | 33 | 28 | 25 | 36 | 33 | 28 | 31 | 30 | ||||
Grade | 1.000 | 0.029 | 1.000 | 0.436 | |||||||||
low | 6 | 3 | 3 | 0 | 6 | 3 | 3 | 4 | 2 | ||||
high | 91 | 43 | 48 | 45 | 46 | 49 | 42 | 44 | 47 | ||||
Tumor stage | 0.055 | 0.007 | 0.179 | 0.001 | |||||||||
pTa–pT1 | 28 | 9 | 19 | 7 | 21 | 18 | 10 | 21 | 7 | ||||
pT2–pT4 | 69 | 37 | 32 | 38 | 31 | 34 | 35 | 27 | 42 |
Spearman’s rho | HER2 (TCs) | IDO (TCs) | PD-L1 (TCs) | PD-L1 (ICs) | CD43 (ICs) | CD8 (ICs) | |
---|---|---|---|---|---|---|---|
HER2 (TCs) | Correlation coefficient | 1.000 | 0.193 | −0.110 | −0.155 | −0.091 | −0.021 |
Sig. (2-tailed) * | - | 0.058 | 0.283 | 0.129 | 0.485 | 0.875 | |
No. | 97 | 97 | 97 | 97 | 61 | 61 | |
IDO (TCs) | Correlation coefficient | 0.193 | 1.000 | −0.171 | −0.259 * | −0.247 | −0.126 |
Sig. (2-tailed) * | 0.058 | - | 0.094 | 0.010 | 0.055 | 0.334 | |
No. | 97 | 97 | 97 | 97 | 61 | 61 | |
PD-L1 (TCs) | Correlation coefficient | −0.110 | −0.171 | 1.000 | 0.383 ** | 0.242 | 0.175 |
Sig. (2-tailed) * | 0.283 | 0.094 | - | 0.000 | 0.060 | 0.177 | |
No. | 97 | 97 | 97 | 97 | 61 | 61 | |
PD-L1 (ICs) | Correlation coefficient | −0.155 | −0.259 * | 0.383 ** | 1.000 | 0.429 ** | 0.470 ** |
Sig. (2-tailed) * | 0.129 | 0.010 | 0.000 | - | 0.001 | 0.000 | |
No. | 97 | 97 | 97 | 97 | 61 | 61 | |
CD43 (ICs) | Correlation coefficient | −0.091 | −0.247 | 0.242 | 0.429 ** | 1.000 | 0.608 ** |
Sig. (2-tailed) * | 0.485 | 0.055 | 0.060 | 0.001 | - | 0.000 | |
No. | 61 | 61 | 61 | 61 | 61 | 61 | |
CD8 (ICs) | Correlation coefficient | −0.021 | −0.126 | 0.175 | 0.470 ** | 0.608 ** | 1.000 |
Sig. (2-tailed) * | 0.875 | 0.334 | 0.177 | 0.000 | 0.000 | - | |
No. | 61 | 61 | 61 | 61 | 61 | 61 |
Overall Survival | Disease-free Survival | |||||
---|---|---|---|---|---|---|
P * | HR | 95% CI | P * | HR | 95% CI | |
HER2 expression (TCs) | 0.143 | 0.028 | ||||
Low | 1 (reference) | 1 (reference) | ||||
High | 1.792 | 0.822–3.907 | 2.381 | 1.097–5.169 | ||
IDO expression (TCs) | 0.683 | 0.048 | ||||
Low | 1 (reference) | 1 (reference) | ||||
High | 0.850 | 0.390–1.852 | 2.158 | 1.007–4.622 | ||
PD-L1 expression (TCs) | 0.854 | 0.291 | ||||
Low | 1 (reference) | 1 (reference) | ||||
High | 1.075 | 0.498–2.320 | 0.664 | 0.311–1.420 | ||
PD-L1 expression (ICs) | 0.741 | 0.333 | ||||
Low | 1 (reference) | 1 (reference) | ||||
High | 1.146 | 0.510–2.577 | 0.692 | 0.329–1.458 | ||
Gender | 0.360 | 0.164 | ||||
Male | 1 (reference) | 1 (reference) | ||||
Female | 0.605 | 0.206–1.774 | 0.425 | 0.128–1.417 | ||
Age (years) | 0.357 | 0.922 | ||||
≤65 | 1 (reference) | 1 (reference) | ||||
>65 | 1.481 | 0.643–3.413 | 0.962 | 0.444–2.085 | ||
Tumor stage | 0.016 | 0.804 | ||||
pT2 | 1 (reference) | 1 (reference) | ||||
pT3–pT4 | 2.639 | 1.196–5.824 | 1.100 | 0.520–2.326 | ||
Radiation therapy after surgery | 0.395 | 0.716 | ||||
No | 1 (reference) | 1 (reference) | ||||
Yes | 0.706 | 0.316–1.576 | 0.870 | 0.410–1.844 |
Overall Survival | Disease-free Survival | |||||
---|---|---|---|---|---|---|
P | HR | 95% CI | P | HR | 95% CI | |
HER2 expression (TCs) | 0.031 | 0.019 | ||||
Low | 1 (reference) | 1 (reference) | ||||
High | 2.501 | 1.090–5.743 | 2.729 | 0.076–6.332 | ||
IDO expression (TCs) | 0.545 | 0.101 | ||||
Low | 1 (reference) | 1 (reference) | ||||
High | 0.772 | 0.334–1.786 | 1.988 | 0.876–4.514 | ||
Gender | 0.350 | 0.054 | ||||
Male | 1 (reference) | 1 (reference) | ||||
Female | 0.576 | 0.181–1.833 | 0.283 | 0.078–1.024 | ||
Age (years) | 0.107 | 0.858 | ||||
≤65 | 1 (reference) | 1 (reference) | ||||
>65 | 2.036 | 0.858–4.833 | 1.079 | 0.470–2.476 | ||
Tumor stage | 0.045 | 0.886 | ||||
pT2 | 1 (reference) | 1 (reference) | ||||
pT3–pT4 | 2.424 | 1.020–5.760 | 0.942 | 0.419–2.118 | ||
Radiation therapy after surgery | 0.744 | 0.505 | ||||
No | 1 (reference) | 1 (reference) | ||||
Yes | 0.867 | 0.369–2.039 | 0.766 | 0.350–1.675 |
© 2020 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/).
Share and Cite
Kim, D.; Kim, J.M.; Kim, J.-S.; Kim, S.; Kim, K.-H. Differential Expression and Clinicopathological Significance of HER2, Indoleamine 2,3-Dioxygenase and PD-L1 in Urothelial Carcinoma of the Bladder. J. Clin. Med. 2020, 9, 1265. https://doi.org/10.3390/jcm9051265
Kim D, Kim JM, Kim J-S, Kim S, Kim K-H. Differential Expression and Clinicopathological Significance of HER2, Indoleamine 2,3-Dioxygenase and PD-L1 in Urothelial Carcinoma of the Bladder. Journal of Clinical Medicine. 2020; 9(5):1265. https://doi.org/10.3390/jcm9051265
Chicago/Turabian StyleKim, Donghyun, Jin Man Kim, Jun-Sang Kim, Sup Kim, and Kyung-Hee Kim. 2020. "Differential Expression and Clinicopathological Significance of HER2, Indoleamine 2,3-Dioxygenase and PD-L1 in Urothelial Carcinoma of the Bladder" Journal of Clinical Medicine 9, no. 5: 1265. https://doi.org/10.3390/jcm9051265