Prognostic Impact of Tumor-Associated Macrophages on Long-Term Oncologic Outcomes in Colorectal Cancer
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients and Tissue Samples
2.2. Evaluation Parameters
2.3. Tissue Microarray Construction
2.4. Immunohistochemistry (IHC)
2.5. Assessment of IHC Staining for TAMs
2.6. Statistical Analyses
2.7. Survival Analysis Using Public CRC Datasets
3. Results
3.1. Characteristics of the Patients
3.2. Clinical Significance of Macrophage Infiltration
3.3. Prognostic Significance of CD68-, CD11c-, and CD163-Positive Macrophages
3.4. Public Dataset Analysis
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
- Arnold, M.; Sierra, M.S.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Patterns and Trends in Colorectal Cancer Incidence and Mortality. Gut 2017, 66, 683–691. [Google Scholar] [CrossRef] [Green Version]
- Shin, A.; Kim, K.Z.; Jung, K.W.; Park, S.; Won, Y.J.; Kim, J.; Kim, D.Y.; Oh, J.H. Increasing Trend of Colorectal Cancer Incidence in Korea, 1999–2009. Cancer Res. Treat. 2012, 44, 219–226. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Colussi, D.; Brandi, G.; Bazzoli, F.; Ricciardiello, L. Molecular Pathways Involved in Colorectal Cancer: Implications for Disease Behavior and Prevention. Int. J. Mol. Sci. 2013, 14, 16365–16385. [Google Scholar] [CrossRef] [Green Version]
- Di Caro, G.; Marchesi, F.; Laghi, L.; Grizzi, F. Immune Cells: Plastic Players Along Colorectal Cancer Progression. J. Cell. Mol. Med. 2013, 17, 1088–1095. [Google Scholar] [CrossRef]
- Ogino, S.; Galon, J.; Fuchs, C.S.; Dranoff, G. Cancer Immunology—Analysis of Host and Tumor Factors for Personalized Medicine. Nat. Rev. Clin. Oncol. 2011, 8, 711–719. [Google Scholar] [CrossRef]
- Yang, J.; Li, X.; Liu, X.; Liu, Y. The Role of Tumor-Associated Macrophages in Breast Carcinoma Invasion and Metastasis. Int. J. Clin. Exp. Pathol. 2015, 8, 6656–6664. [Google Scholar]
- Mantovani, A.; Sozzani, S.; Locati, M.; Allavena, P.; Sica, A. Macrophage Polarization: Tumor-Associated Macrophages as a Paradigm for Polarized M2 Mononuclear Phagocytes. Trends Immunol. 2002, 23, 549–555. [Google Scholar] [CrossRef]
- Mantovani, A.; Allavena, P. The Interaction of Anticancer Therapies with Tumor-Associated Macrophages. J. Exp. Med. 2015, 212, 435–445. [Google Scholar] [CrossRef] [PubMed]
- Liu, C.; Li, Y.; Yu, J.; Feng, L.; Hou, S.; Liu, Y.; Guo, M.; Xie, Y.; Meng, J.; Zhang, H.; et al. Targeting the Shift from M1 to M2 Macrophages in Experimental Autoimmune Encephalomyelitis Mice Treated with Fasudil. PLoS ONE 2013, 8, e54841. [Google Scholar] [CrossRef] [Green Version]
- Wei, C.; Yang, C.; Wang, S.; Shi, D.; Zhang, C.; Lin, X.; Liu, Q.; Dou, R.; Xiong, B. Crosstalk Between Cancer Cells and Tumor Associated Macrophages is Required for Mesenchymal Circulating Tumor Cell-Mediated Colorectal Cancer Metastasis. Mol. Cancer 2019, 18, 64. [Google Scholar] [CrossRef]
- Yahaya, M.A.F.; Lila, M.A.M.; Ismail, S.; Zainol, M.; Afizan, N. Tumour-Associated Macrophages (TAMs) in Colon Cancer and How to Reeducate Them. J. Immunol. Res. 2019, 2019, 2368249. [Google Scholar] [CrossRef] [PubMed]
- Inagaki, K.; Kunisho, S.; Takigawa, H.; Yuge, R.; Oka, S.; Tanaka, S.; Shimamoto, F.; Chayama, K.; Kitadai, Y. Role of Tumor-Associated Macrophages at the Invasive Front in Human Colorectal Cancer Progression. Cancer Sci. 2021, 112, 2692–2704. [Google Scholar] [CrossRef]
- Amin, M.B.; Greene, F.L.; Edge, S.B.; Compton, C.C.; Gershenwald, J.E.; Brookland, R.K.; Meyer, L.; Gress, D.M.; Byrd, D.R.; Winchester, D.P. The Eighth Edition AJCC Cancer Staging Manual: Continuing to Build a Bridge from a Population-Based to a More “Personalized” Approach to Cancer Staging. CA Cancer J. Clin. 2017, 67, 93–99. [Google Scholar] [CrossRef] [PubMed]
- Available online: https://www.r-project.org/ (accessed on 10 June 2021).
- Newman, A.M.; Steen, C.B.; Liu, C.L.; Gentles, A.J.; Chaudhuri, A.A.; Scherer, F.; Khodadoust, M.S.; Esfahani, M.S.; Luca, B.A.; Steiner, D.; et al. Determining Cell Type Abundance and Expression from Bulk Tissues with Digital Cytometry. Nat. Biotechnol. 2019, 37, 773–782. [Google Scholar] [CrossRef]
- Sturm, G.; Finotello, F.; Petitprez, F.; Zhang, J.D.; Baumbach, J.; Fridman, W.H.; List, M.; Aneichyk, T. Comprehensive Evaluation of Transcriptome-Based Cell-Type Quantification Methods for Immuno-Oncology. Bioinformatics 2019, 35, i436–i445. [Google Scholar] [CrossRef] [PubMed]
- Biswas, S.K.; Gangi, L.; Paul, S.; Schioppa, T.; Saccani, A.; Sironi, M.; Bottazzi, B.; Doni, A.; Vincenzo, B.; Pasqualini, F.; et al. A Distinct and Unique Transcriptional Program Expressed by Tumor-Associated Macrophages (Defective NF-KappaB and Enhanced IRF-3/STAT1 Activation). Blood 2006, 107, 2112–2122. [Google Scholar] [CrossRef] [Green Version]
- Noy, R.; Pollard, J.W. Tumor-Associated Macrophages: From Mechanisms to Therapy. Immunity 2014, 41, 49–61. [Google Scholar] [CrossRef] [Green Version]
- Zhong, X.; Chen, B.; Yang, Z. The Role of Tumor-Associated Macrophages in Colorectal Carcinoma Progression. Cell. Physiol. Biochem. 2018, 45, 356–365. [Google Scholar] [CrossRef]
- Hu, H.; Hang, J.J.; Han, T.; Zhuo, M.; Jiao, F.; Wang, L.W. The M2 Phenotype of Tumor-Associated Macrophages in the Stroma Confers a Poor Prognosis in Pancreatic Cancer. Tumour Biol. 2016, 37, 8657–8664. [Google Scholar] [CrossRef]
- Mei, J.; Xiao, Z.; Guo, C.; Pu, Q.; Ma, L.; Liu, C.; Lin, F.; Liao, H.; You, Z.; Liu, L. Prognostic Impact of Tumor-Associated Macrophage Infiltration in Non-Small Cell Lung Cancer: A Systemic Review and Meta-Analysis. Oncotarget 2016, 7, 34217–34228. [Google Scholar] [CrossRef] [Green Version]
- Li, J.; Li, L.; Li, Y.; Long, Y.; Zhao, Q.; Ouyang, Y.; Bao, W.; Gong, K. Tumor-associated macrophage infiltration and prognosis in colorectal cancer: Systematic review and meta-analysis. Int. J. Colorectal Dis. 2020, 35, 1203–1210. [Google Scholar] [CrossRef]
- Wang, H.; Tian, T.; Zhang, J. Tumor-Associated Macrophages (TAMs) in Colorectal Cancer (CRC): From Mechanism to Therapy and Prognosis. Int. J. Mol. Sci. 2021, 22, 8470. [Google Scholar] [CrossRef] [PubMed]
- Gautier, E.L.; Shay, T.; Miller, J.; Greter, M.; Jakubzick, C.; Ivanov, S.; Helft, J.; Chow, A.; Elpek, K.G.; Gordonov, S.; et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 2012, 13, 1118–1128. [Google Scholar] [CrossRef] [Green Version]
- Gulubova, M.; Aleksandrova, E.; Vlaykova, T. Promoter polymorphisms in TGFB1 and IL10 genes influence tumor dendritic cells infiltration, development and prognosis of colorectal cancer. J. Gene Med. 2018, 20, e3005. [Google Scholar] [CrossRef] [PubMed]
- Shu, Q.H.; Ge, Y.S.; Ma, H.X.; Gao, X.Q.; Pan, J.J.; Liu, D.; Xu, G.L.; Ma, J.L.; Jia, W.D. Prognostic value of polarized macrophages in patients with hepatocellular carcinoma after curative resection. J. Cell. Mol. Med. 2016, 20, 1024–1035. [Google Scholar] [CrossRef] [PubMed]
- Jeong, H.; Hwang, I.; Kang, S.H.; Shin, H.C.; Kwon, S.Y. Tumor-Associated Macrophages as Potential Prognostic Biomarkers of Invasive Breast Cancer. J. Breast Cancer 2019, 22, 38–51. [Google Scholar] [CrossRef]
- Gordon, S.R.; Maute, R.L.; Dulken, B.W.; Hutter, G.; George, B.M.; McCracken, M.N.; Gupta, R.; Tsai, J.M.; Sinha, R.; Corey, D.; et al. PD-1 Expression by Tumour-Associated Macrophages Inhibits Phagocytosis and Tumour Immunity. Nature 2017, 545, 495–499. [Google Scholar] [CrossRef]
Clinicopathologic Features | n = 148 | CD68 Positive | CD11c Positive | CD163 Positive | |||
---|---|---|---|---|---|---|---|
Mean ± SD | p-Value | Mean ± SD | p-Value | Mean ± SD | p-Value | ||
Age (mean) | 32–92 (67.2) | ||||||
Gender | |||||||
Male | 92 | 63.36 ± 31.83 | 0.31 | 66.32 ± 30.60 | 0.87 | 42.6 ± 23.07 | 0.33 |
Female | 56 | 76.07 ± 38.27 | 75.34 ± 31.27 | 51.07 ± 25.77 | |||
T Stage | |||||||
1, 2 | 28 | 67.40 ± 36.36 | 0.9 | 72.94 ± 35.91 | 0.55 | 43.40 ± 21.22 | 0.6 |
3, 4 | 120 | 68.34 ± 34.62 | 68.98 ± 29.93 | 46.10 ± 25.16 | |||
LN metastasis | |||||||
Absent | 70 | 68.00 + 36.81 | 0.96 | 70.15 ± 32.22 | 0.88 | 44.13 ± 20.92 | 0.49 |
Present | 78 | 68.32 ± 33.20 | 69.35 ± 30.19 | 46.90 ± 27.25 | |||
Distant metastasis | |||||||
Absent | 133 | 65.81 ± 33.78 | 0.01 | 69.40 ± 32.07 | 0.7 | 45.07 ± 23.80 | 0.44 |
Present | 15 | 89.02 ± 38.26 | 72.69 ± 20.62 | 50.23 ± 29.90 | |||
Differentiation | |||||||
Well and moderate | 138 | 68.02 ± 33.75 | 0.85 | 70.09 ± 31.62 | 0.61 | 45.48 ± 24.41 | 0.84 |
Poorly and mucinous | 10 | 70.23 ± 49.75 | 64.80 ± 22.64 | 47.1 ± 25.89 |
Variables | OS | DFS | ||||
---|---|---|---|---|---|---|
HR | 95% CI | p-Value | HR | 95% CI | p-Value | |
Age | 1.018 | 0.988–1.049 | 0.247 | 1.003 | 0.980–1.027 | 0.795 |
Gender (Male vs. Female) | 0.815 | 0.410–1.617 | 0.558 | 0.772 | 0.441–1.351 | 0.364 |
T stage (stage 1, 2 vs. stage 3, 4) | 2.231 | 0.653–7615 | 0.200 | 2.136 | 0.827–5.519 | 0.117 |
Lymph node metastasis (+ vs. −) | 2.144 | 0.977–4.707 | 0.057 | 3.534 | 1.849–6.751 | 0.000 |
Distant metastasis (+ vs. −) | 4.847 | 1.959–11.990 | 0.001 | 5.97 × 105 | 0.000–3.00 × 1073 | 0.867 |
Differentiation (Well and moderate vs. poorly and mucinous) | 2.089 | 0.599–7.285 | 0.248 | 1.884 | 0.767–4.630 | 0.167 |
CD68 | 1.005 | 0.994–1.017 | 0.362 | 1.003 | 0.993–1.013 | 0.550 |
CD11c | 0.985 | 0.972–0.999 | 0.032 | 0.990 | 0.980–1.001 | 0.063 |
CD163 | 1.002 | 0.990–1.014 | 0.747 | 0.999 | 0.988–1.010 | 0.848 |
Variables | OS | ||
---|---|---|---|
HR | 95% CI | p-Value | |
Lymph node metastasis (+ vs. −) | 2.425 | 1.139–5.167 | 0.022 |
Distant metastasis (+ vs. −) | 4.464 | 2.087–9.548 | 0.000 |
CD11c | 0.988 | 0.977–0.999 | 0.040 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 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 (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Shin, H.C.; Seo, I.; Jeong, H.; Byun, S.J.; Kim, S.; Bae, S.U.; Kwon, S.Y.; Lee, H.W. Prognostic Impact of Tumor-Associated Macrophages on Long-Term Oncologic Outcomes in Colorectal Cancer. Life 2021, 11, 1240. https://doi.org/10.3390/life11111240
Shin HC, Seo I, Jeong H, Byun SJ, Kim S, Bae SU, Kwon SY, Lee HW. Prognostic Impact of Tumor-Associated Macrophages on Long-Term Oncologic Outcomes in Colorectal Cancer. Life. 2021; 11(11):1240. https://doi.org/10.3390/life11111240
Chicago/Turabian StyleShin, Hyeong Chan, Incheol Seo, Hasong Jeong, Sang Jun Byun, Shin Kim, Sung Uk Bae, Sun Young Kwon, and Hye Won Lee. 2021. "Prognostic Impact of Tumor-Associated Macrophages on Long-Term Oncologic Outcomes in Colorectal Cancer" Life 11, no. 11: 1240. https://doi.org/10.3390/life11111240