Tumor B7-H3 (CD276) Expression and Survival in Pancreatic Cancer
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients
2.2. B7-H3 Immunohistochemistry
2.3. Statistical Analysis
3. Results
3.1. Tumor B7-H3 Expression in Pancreatic Cancer
3.2. B7-H3 Expression Status and Survival in Patients with Pancreatic Cancer
3.3. Effects of Clinicopathological Variables on B7-H3 Expression and Survival
4. Discussion
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
CI | confidence interval |
DFS | disease-free survival |
HR | hazard ratio |
JFCR | Japanese Foundation for Cancer Research |
NSCLC | non-small-cell lung cancer |
p-stage | pathological stage |
TMA | tissue microarray |
References
- Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer Statistics, 2017. CA Cancer J. Clin. 2017, 67, 7–30. [Google Scholar] [CrossRef] [PubMed]
- Ryan, D.P.; Hong, T.S.; Bardeesy, N. Pancreatic adenocarcinoma. N. Engl. J. Med. 2014, 371, 1039–1049. [Google Scholar] [CrossRef] [PubMed]
- Maitra, A.; Hruban, R.H. Pancreatic cancer. Annu. Rev. Pathol. 2008, 3, 157–188. [Google Scholar] [CrossRef] [PubMed]
- Vonderheide, R.H.; Bayne, L.J. Inflammatory networks and immune surveillance of pancreatic carcinoma. Curr. Opin. Immunol. 2013, 25, 200–205. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Orozco, C.A.; Martinez-Bosch, N.; Guerrero, P.E.; Vinaixa, J.; Dalotto-Moreno, T.; Iglesias, M.; Moreno, M.; Djurec, M.; Poirier, F.; Gabius, H.J.; et al. Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor-stroma crosstalk. Proc. Natl. Acad. Sci. USA 2018, 115, E3769–E3778. [Google Scholar] [CrossRef] [PubMed]
- Xu, J.W.; Wang, L.; Cheng, Y.G.; Zhang, G.Y.; Hu, S.Y.; Zhou, B.; Zhan, H.X. Immunotherapy for pancreatic cancer: A long and hopeful journey. Cancer Lett. 2018, 425, 143–151. [Google Scholar] [CrossRef] [PubMed]
- Wartenberg, M.; Cibin, S.; Zlobec, I.; Vassella, E.; Eppenberger-Castori, S.M.M.; Terracciano, L.; Eichmann, M.; Worni, M.; Gloor, B.; Perren, A.; et al. Integrated genomic and immunophenotypic classification of pancreatic cancer reveals three distinct subtypes with prognostic/predictive significance. Clin. Cancer Res. 2018. Available online: https://www.ncbi.nlm.nih.gov/pubmed/29661773 (accessed on 1 June 2018).
- Bishehsari, F.; Zhang, L.; Barlass, U.; Preite, N.; Turturro, S.; Najor, M.S.; Shetuni, B.B.; Zayas, J.P.; Mahdavinia, M.; Abukhdeir, A.M.; et al. KRAS Mutation and Epithelial-Macrophage Interplay in Pancreatic Neoplastic Transformation. Int. J. Cancer. 2018. Available online: https://www.ncbi.nlm.nih.gov/pubmed/29756386 (accessed on 1 June 2018).
- Veenstra, V.L.; Garcia-Garijo, A.; van Laarhoven, H.W.; Bijlsma, M.F. Extracellular Influences: Molecular Subclasses and the Microenvironment in Pancreatic Cancer. Cancers (Basel) 2018, 10, 34. [Google Scholar] [CrossRef] [PubMed]
- Mei, L.; Du, W.; Ma, W.W. Targeting stromal microenvironment in pancreatic ductal adenocarcinoma: controversies and promises. J. Gastrointest. Oncol. 2016, 7, 487–494. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Forde, P.M.; Chaft, J.E.; Smith, K.N.; Anagnostou, V.; Cottrell, T.R.; Hellmann, M.D.; Zahurak, M.; Yang, S.C.; Jones, D.R.; Broderick, S.; et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N. Engl. J. Med. 2018, 378, 1976–1986. [Google Scholar] [CrossRef] [PubMed]
- Tie, Y.; Ma, X.; Zhu, C.; Mao, Y.; Shen, K.; Wei, X.; Chen, Y.; Zheng, H. Safety and efficacy of nivolumab in the treatment of cancers: A meta-analysis of 27 prospective clinical trials. Int. J. Cancer 2017, 140, 948–958. [Google Scholar] [CrossRef] [PubMed]
- Martinez-Bosch, N.; Vinaixa, J.; Navarro, P. Immune Evasion in Pancreatic Cancer: From Mechanisms to Therapy. Cancers (Basel) 2018, 10, 6. [Google Scholar] [CrossRef] [PubMed]
- Zhang, J.; Wolfgang, C.L.; Zheng, L. Precision Immuno-Oncology: Prospects of Individualized Immunotherapy for Pancreatic Cancer. Cancers (Basel) 2018, 10, 39. [Google Scholar] [CrossRef] [PubMed]
- Foley, K.; Kim, V.; Jaffee, E.; Zheng, L. Current progress in immunotherapy for pancreatic cancer. Cancer Lett. 2016, 381, 244–251. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Brahmer, J.R.; Tykodi, S.S.; Chow, L.Q.; Hwu, W.J.; Topalian, S.L.; Hwu, P.; Drake, C.G.; Camacho, L.H.; Kauh, J.; Odunsi, K.; et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 2012, 366, 2455–2465. [Google Scholar] [CrossRef] [PubMed]
- Royal, R.E.; Levy, C.; Turner, K.; Mathur, A.; Hughes, M.; Kammula, U.S.; Sherry, R.M.; Topalian, S.L.; Yang, J.C.; Lowy, I.; et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J. Immunother. 2010, 33, 828–833. [Google Scholar] [CrossRef] [PubMed]
- Balachandran, V.P.; Luksza, M.; Zhao, J.N.; Makarov, V.; Moral, J.A.; Remark, R.; Herbst, B.; Askan, G.; Bhanot, U.; Senbabaoglu, Y.; et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 2017, 551, 512–516. [Google Scholar] [CrossRef] [PubMed]
- Wang, L.; Kang, F.B.; Shan, B.E. B7-H3-mediated tumor immunology: Friend or foe? Int. J. Cancer 2014, 134, 2764–2771. [Google Scholar] [CrossRef] [PubMed]
- Chapoval, A.I.; Ni, J.; Lau, J.S.; Wilcox, R.A.; Flies, D.B.; Liu, D.; Dong, H.; Sica, G.L.; Zhu, G.; Tamada, K.; et al. B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Nat. Immunol. 2001, 2, 269–274. [Google Scholar] [CrossRef] [PubMed]
- Sun, M.; Richards, S.; Prasad, D.V.; Mai, X.M.; Rudensky, A.; Dong, C. Characterization of mouse and human B7-H3 genes. J. Immunol. 2002, 168, 6294–6297. [Google Scholar] [CrossRef] [PubMed]
- Yonesaka, K.; Haratani, K.; Takamura, S.; Sakai, H.; Kato, R.; Takegawa, N.; Takahama, T.; Tanaka, K.; Hayashi, H.; Takeda, M.; et al. B7-H3 Negatively Modulates CTL-Mediated Cancer Immunity. Clin. Cancer Res. 2018, 24, 2653–2664. [Google Scholar] [CrossRef] [PubMed]
- Marmarelis, M.E.; Aggarwal, C. Combination Immunotherapy in Non-small Cell Lung Cancer. Curr. Oncol. Rep. 2018, 20, 55. [Google Scholar] [CrossRef] [PubMed]
- Marin-Acevedo, J.A.; Dholaria, B.; Soyano, A.E.; Knutson, K.L.; Chumsri, S.; Lou, Y. Next generation of immune checkpoint therapy in cancer: new developments and challenges. J. Hematol. Oncol. 2018, 11, 39. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ignatiadis, M.; Van den Eynden, G.; Roberto, S.; Fornili, M.; Bareche, Y.; Desmedt, C.; Rothe, F.; Maetens, M.; Venet, D.; Holgado, E.; et al. Tumor-Infiltrating Lymphocytes in Patients Receiving Trastuzumab/Pertuzumab-Based Chemotherapy: A TRYPHAENA Substudy. Natl. Cancer Inst. 2018. Available online: https://www.ncbi.nlm.nih.gov/pubmed/29788230 (accessed on 1 June 2018).
- Seaman, S.; Zhu, Z.; Saha, S.; Zhang, X.M.; Yang, M.Y.; Hilton, M.B.; Morris, K.; Szot, C.; Morris, H.; Swing, D.A.; et al. Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3-Positive Tumor Cells and Tumor Vasculature. Cancer Cell 2017, 31, 501–515. [Google Scholar] [CrossRef] [PubMed]
- Burugu, S.; Dancsok, A.R.; Nielsen, T.O. Emerging targets in cancer immunotherapy. Semin. Cancer Biol. 2017. Available online: https://www.ncbi.nlm.nih.gov/pubmed/28987965 (accessed on 1 June 2018).
- Picarda, E.; Ohaegbulam, K.C.; Zang, X. Molecular Pathways: Targeting B7-H3 (CD276) for Human Cancer Immunotherapy. Clin. Cancer Res. 2016, 22, 3425–3431. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yamato, I.; Sho, M.; Nomi, T.; Akahori, T.; Shimada, K.; Hotta, K.; Kanehiro, H.; Konishi, N.; Yagita, H.; Nakajima, Y. Clinical importance of B7-H3 expression in human pancreatic cancer. Br. J. Cancer 2009, 101, 1709–1716. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Loos, M.; Hedderich, D.M.; Ottenhausen, M.; Giese, N.A.; Laschinger, M.; Esposito, I.; Kleeff, J.; Friess, H. Expression of the costimulatory molecule B7-H3 is associated with prolonged survival in human pancreatic cancer. BMC Cancer 2009, 9, 463. [Google Scholar] [CrossRef] [PubMed]
- Li, D.; Wang, J.; Zhou, J.; Zhan, S.; Huang, Y.; Wang, F.; Zhang, Z.; Zhu, D.; Zhao, H.; Li, D.; et al. B7-H3 combats apoptosis induced by chemotherapy by delivering signals to pancreatic cancer cells. Oncotarget 2017, 8, 74856–74868. [Google Scholar] [CrossRef] [PubMed]
- Xu, H.; Chen, X.; Tao, M.; Chen, K.; Chen, C.; Xu, G.; Li, W.; Yuan, S.; Mao, Y. B7-H3 and B7-H4 are independent predictors of a poor prognosis in patients with pancreatic cancer. Oncol. Lett. 2016, 11, 1841–1846. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chen, Y.; Sun, J.; Zhao, H.; Zhu, D.; Zhi, Q.; Song, S.; Zhang, L.; He, S.; Kuang, Y.; Zhang, Z.; et al. The coexpression and clinical significance of costimulatory molecules B7-H1, B7-H3, and B7-H4 in human pancreatic cancer. OncoTargets Ther. 2014, 7, 1465–1472. [Google Scholar] [CrossRef] [PubMed]
- Xu, L.; Ding, X.; Tan, H.; Qian, J. Correlation between B7-H3 expression and matrix metalloproteinases 2 expression in pancreatic cancer. Cancer Cell Int. 2013, 13, 81. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, X.; Fang, C.; Zhang, G.; Jiang, F.; Wang, L.; Hou, J. Prognostic value of B7-H3 expression in patients with solid tumors: a meta-analysis. Oncotarget 2017, 8, 93156–93167. [Google Scholar] [CrossRef] [PubMed]
- Amin, M.B.; Edge, S.B.; Greene, F.L.; Byrd, D.R.; Brookland, R.K.; Washington, M.K.; Gershenwald, J.E.; Compton, C.C.; Hess, K.R.; Sullivan, D.C.; et al. AJCC Cancer Staging Manual, 8th ed.; Springer: New York, NY, USA, 2017. [Google Scholar]
- Hiramatsu, M.; Ninomiya, H.; Inamura, K.; Nomura, K.; Takeuchi, K.; Satoh, Y.; Okumura, S.; Nakagawa, K.; Yamori, T.; Matsuura, M.; et al. Activation status of receptor tyrosine kinase downstream pathways in primary lung adenocarcinoma with reference of KRAS and EGFR mutations. Lung Cancer 2010, 70, 94–102. [Google Scholar] [CrossRef] [PubMed]
- Inamura, K.; Yokouchi, Y.; Kobayashi, M.; Sakakibara, R.; Ninomiya, H.; Subat, S.; Nagano, H.; Nomura, K.; Okumura, S.; Shibutani, T.; et al. Tumor B7-H3 (CD276) expression and smoking history in relation to lung adenocarcinoma prognosis. Lung Cancer 2017, 103, 44–51. [Google Scholar] [CrossRef] [PubMed]
- Inamura, K.; Yokouchi, Y.; Sakakibara, R.; Kobayashi, M.; Subat, S.; Ninomiya, H.; Nagano, H.; Nomura, K.; Okumura, S.; Ishikawa, Y. Relationship of tumor PD-L1 expression with EGFR wild-type status and poor prognosis in lung adenocarcinoma. Jpn. J. Clin. Oncol. 2016, 46, 935–941. [Google Scholar] [CrossRef] [PubMed]
- Pylayeva-Gupta, Y.; Lee, K.E.; Hajdu, C.H.; Miller, G.; Bar-Sagi, D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 2012, 21, 836–847. [Google Scholar] [CrossRef] [PubMed]
- Vigdorovich, V.; Ramagopal, U.A.; Lazar-Molnar, E.; Sylvestre, E.; Lee, J.S.; Hofmeyer, K.A.; Zang, X.; Nathenson, S.G.; Almo, S.C. Structure and T cell inhibition properties of B7 family member, B7-H3. Structure 2013, 21, 707–717. [Google Scholar] [CrossRef] [PubMed]
- Zhao, X.; Li, D.C.; Zhu, X.G.; Gan, W.J.; Li, Z.; Xiong, F.; Zhang, Z.X.; Zhang, G.B.; Zhang, X.G.; Zhao, H. B7-H3 overexpression in pancreatic cancer promotes tumor progression. Int. J. Mol. Med. 2013, 31, 283–291. [Google Scholar] [CrossRef] [PubMed]
- Ingebrigtsen, V.A.; Boye, K.; Nesland, J.M.; Nesbakken, A.; Flatmark, K.; Fodstad, O. B7-H3 expression in colorectal cancer: associations with clinicopathological parameters and patient outcome. BMC Cancer 2014, 14, 602. [Google Scholar] [CrossRef] [PubMed]
- Kraan, J.; Van den Broek, P.; Verhoef, C.; Grunhagen, D.J.; Taal, W.; Gratama, J.W.; Sleijfer, S. Endothelial CD276 (B7-H3) expression is increased in human malignancies and distinguishes between normal and tumour-derived circulating endothelial cells. Br. J. Cancer 2014, 111, 149–156. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Variables | N of Samples (%) | B7-H3 Expression | |||
---|---|---|---|---|---|
Negative N = 51 (34%) | Positive N = 99 (66%) | P Values | |||
Age | 1.00 | ||||
≤65 years | 60 (40%) | 20 (39%) | 40 (40%) | ||
>65 years | 90 (60%) | 31 (61%) | 59 (60%) | ||
Gender | 0.22 | ||||
Male | 89 (59%) | 34 (67%) | 55 (56%) | ||
Female | 61 (41%) | 17 (33%) | 44 (44%) | ||
Body-mass index | 0.78 | ||||
<25 kg/m2 | 134 (89%) | 45 (88%) | 89 (90%) | ||
≥25 kg/m2 | 16 (11%) | 6 (12%) | 10 (10%) | ||
CEA | 0.85 | ||||
≤5 ng/mL | 112 (75%) | 39 (76%) | 73 (74%) | ||
>5 ng/mL | 38 (25%) | 12 (24%) | 26 (26%) | ||
CA19-9 | 0.50 | ||||
<500 U/mL | 88 (68%) | 29 (64%) | 59 (70%) | ||
≥500 U/mL | 41 (32%) | 16 (36%) | 25 (30%) | ||
Tumor location | 0.49 | ||||
Head | 87 (58%) | 32 (63%) | 55 (56%) | ||
Body/tail | 63 (42%) | 19 (37%) | 44 (44%) | ||
Pathological stage | 0.11 | ||||
I–II | 82 (55%) | 33 (63%) | 49 (50%) | ||
III–IV | 68 (45%) | 19 (37%) | 49 (50%) | ||
Adjuvant chemotherapy | 0.73 | ||||
Absent | 32 (22%) | 10 (20%) | 22 (22%) | ||
Present | 116 (78%) | 40 (80%) | 76 (78%) |
Disease-Free Survival | Overall Survival | |||||||
---|---|---|---|---|---|---|---|---|
Univariable Analysis | Multivariable Analysis ** | Univariable Analysis | Multivariable Analysis ** | |||||
HR (95% CI) | P Values | HR (95% CI) | P Values | HR (95% CI) | P Values | HR (95% CI) | P Values | |
B7-H3: positive (vs. negative) | 1.91 (1.31–2.84) | 0.0006 | 1.99 (1.32–3.06) | 0.0009 | 1.66(1.14–2.44) | 0.0074 | 1.69 (1.13–2.57) | 0.011 |
Adjuvant chemotherapy: absent (vs. present) | 1.94 (1.26–2.90) | 0.0032 | 2.10 (1.32–3.25) | 0.0021 | 1.75 (1.14–2.62) | 0.012 | 1.77 (1.11–2.75) | 0.018 |
CA19-9 (U/mL): ≥500 (vs. <500) | 1.85 (1.23–2.75) | 0.0034 | 1.86 (1.23–2.77) | 0.0036 | 1.67 (1.11–2.47) | 0.014 | 1.67 (1.11–2.48) | 0.016 |
Pathological stage: III−IV (vs. I−II) | 1.30 (0.91–1.85) | 0.14 | 1.38 (0.97–1.95) | 0.075 | 1.29 (0.87–1.90) | 0.20 | ||
CEA (ng/mL): >5 (vs. ≤5) | 1.41 (0.94–2.08) | 0.093 | 1.41 (0.92–2.08) | 0.10 | ||||
Gender: female (vs. male) | 1.26 (0.88–1.80) | 0.20 | 1.21 (0.85–1.71) | 0.30 | ||||
Body-mass index (kg/m2): ≥25 (vs. <25) | 1.27 (0.71–2.12) | 0.40 | 1.13 (0.63–1.88) | 0.66 | ||||
Age (years): ≤65 (vs. >65) | 1.09 (0.76–1.56) | 0.63 | 1.02 (0.71–1.45) | 0.93 | ||||
Location of primary tumor: body/tail (vs. head) | 1.02 (0.71–1.45) | 0.91 | 1.00 (0.70–1.42) | 1.00 |
Disease-Free Survival | Overall Survival | |||||||
---|---|---|---|---|---|---|---|---|
Univariable Analysis | Multivariable Analysis ** | Univariable Analysis | Multivariable Analysis ** | |||||
HR (95% CI) | P Values | HR (95% CI) | P Values | HR (95% CI) | P Values | HR (95% CI) | P Values | |
B7-H3 negative (N = 51) | 1 (referent) | 1 (referent) | 1 (referent) | 1 (referent) | ||||
B7-H3 low (N = 67) | 1.78 (1.18–2.70) | 0.0056 | 1.79 (1.14–2.82) | 0.011 | 1.63 (1.09–2.46) | 0.017 | 1.64 (1.05–2.59) | 0.028 |
B7-H3 intermediate (N = 20) | 1.97 (1.10–3.42) | 0.024 | 2.41 (1.26–4.40) | 0.0092 | 1.49 (0.82–2.59) | 0.19 | 1.66 (0.86–3.07) | 0.12 |
B7-H3 high (N = 12) | 2.97 (1.47–5.59) | 0.0035 | 3.12 (1.48–6.15) | 0.0039 | 2.21 (1.10–4.11) | 0.027 | 2.21 (1.06–4.28) | 0.036 |
P values for trend | 0.044 | 0.0026 | 0.040 | 0.055 |
Disease-Free Survival | Overall Survival | ||||||||
---|---|---|---|---|---|---|---|---|---|
Univariable Analysis | Multivariable Analysis ** | Univariable Analysis | Multivariable Analysis ** | ||||||
HR (95% CI) | P Values | HR (95% CI) | P Values | HR (95% CI) | P Values | HR (95% CI) | P Values | ||
Pathological stage: I−II | B7–H3 negative | 1 (referent) | 1 (referent) | 1 (referent) | 1 (referent) | ||||
(N = 93) | B7–H3 positive | 2.55 (1.54–4.34) | 0.0003 | 3.10 (1.75–5.69) | <0.0001 | 2.19 (1.32–3.72) | 0.0021 | 2.59 (1.49–4.67) | 0.0007 |
Pathological stage: III−IV | B7–H3 negative | 1 (referent) | 1 (referent) | 1 (referent) | 1 (referent) | ||||
(N = 57) | B7–H3 positive | 1.19 (0.68–2.18) | 0.54 | 1.20 (0.67–2.28) | 0.55 | 0.99 (0.58–1.76) | 0.96 | 1.03 (0.58–1.88) | 0.93 |
P values for interaction*** | 0.069 | 0.048 | 0.045 | 0.033 |
© 2018 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
Inamura, K.; Takazawa, Y.; Inoue, Y.; Yokouchi, Y.; Kobayashi, M.; Saiura, A.; Shibutani, T.; Ishikawa, Y. Tumor B7-H3 (CD276) Expression and Survival in Pancreatic Cancer. J. Clin. Med. 2018, 7, 172. https://doi.org/10.3390/jcm7070172
Inamura K, Takazawa Y, Inoue Y, Yokouchi Y, Kobayashi M, Saiura A, Shibutani T, Ishikawa Y. Tumor B7-H3 (CD276) Expression and Survival in Pancreatic Cancer. Journal of Clinical Medicine. 2018; 7(7):172. https://doi.org/10.3390/jcm7070172
Chicago/Turabian StyleInamura, Kentaro, Yutaka Takazawa, Yosuke Inoue, Yusuke Yokouchi, Maki Kobayashi, Akio Saiura, Tomoko Shibutani, and Yuichi Ishikawa. 2018. "Tumor B7-H3 (CD276) Expression and Survival in Pancreatic Cancer" Journal of Clinical Medicine 7, no. 7: 172. https://doi.org/10.3390/jcm7070172