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Erschienen in:

09.01.2022 | Urologic Oncology

Stromal Tumor-Associated Macrophage Infiltration Predicts Poor Clinical Outcomes in Muscle-Invasive Bladder Cancer Patients

verfasst von: Shengming Jin, MD, Han Zeng, MD, Zhaopei Liu, MD, Kaifeng Jin, MD, Chunnan Liu, MD, Sen Yan, MD, Yanze Yu, MD, Runze You, MD, Hongyi Zhang, MD, Yuan Chang, MD, Le Xu, PhD, Jiejie Xu, MD, PhD, Zewei Wang, MD, Yu Zhu, PhD

Erschienen in: Annals of Surgical Oncology | Ausgabe 4/2022

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Abstract

Background

This study aims to reveal the clinical significance of stromal-infiltrating tumor-associated macrophages (TAMs) in muscle-invasive bladder cancer (MIBC).

Patients and Methods

This study included 288 patients from the TCGA database and 118 patients from Fudan University Shanghai Cancer Center with MIBC. The CIBERSORT model and immunohistochemistry were used to evaluate TAM infiltration. Cox regression analyses were employed to calculate their prognostic value.

Results

Among all 23 immune phenotypes analyzed in the TCGA cohort, pan-macrophage infiltration was significantly associated with poor prognosis (p = 0.001). Further analyses found that stromal TAM infiltration could be an independent prognostic predictor for recurrence-free survival (RFS; HR: 1.019, 95% CI: 1.006–1.033, p = 0.004). High stromal infiltration was related to unfavorable RFS. After stratification by adjuvant chemotherapy (ACT), patients without ACT could be differentiated by TAM infiltration (p = 0.036), while patients with ACT could not. Moreover, TAM infiltration was negatively associated with IFN-γ-related mRNA panel, which was shown to have strong predictive value for clinical response to programmed death-1 (PD-1) inhibition.

Conclusions

Stromal TAM infiltration could be an independent prognosticator for MIBC patients. This might have potential to guide precise treatments such as ACT and immune checkpoint blockade in MIBC.
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Literatur
1.
Zurück zum Zitat Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.CrossRef Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.CrossRef
2.
Zurück zum Zitat Ghandour R, Singla N, Lotan Y. Treatment options and outcomes in nonmetastatic muscle invasive bladder cancer. Trends Cancer. 2019;5(7):426–39.CrossRef Ghandour R, Singla N, Lotan Y. Treatment options and outcomes in nonmetastatic muscle invasive bladder cancer. Trends Cancer. 2019;5(7):426–39.CrossRef
3.
Zurück zum Zitat Liu D, Abbosh P, Keliher D, et al. Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer. Nat Commun. 2017;8(1):2193.CrossRef Liu D, Abbosh P, Keliher D, et al. Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer. Nat Commun. 2017;8(1):2193.CrossRef
4.
Zurück zum Zitat Vlachostergios PJ, Faltas BM. Treatment resistance in urothelial carcinoma: an evolutionary perspective. Nat Rev Clin Oncol. 2018;15(8):495–509.CrossRef Vlachostergios PJ, Faltas BM. Treatment resistance in urothelial carcinoma: an evolutionary perspective. Nat Rev Clin Oncol. 2018;15(8):495–509.CrossRef
5.
Zurück zum Zitat Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306.CrossRef Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306.CrossRef
6.
Zurück zum Zitat Li S, Xu F, Zhang J, et al. Tumor-associated macrophages remodeling EMT and predicting survival in colorectal carcinoma. Oncoimmunology. 2018;7(2):e1380765.CrossRef Li S, Xu F, Zhang J, et al. Tumor-associated macrophages remodeling EMT and predicting survival in colorectal carcinoma. Oncoimmunology. 2018;7(2):e1380765.CrossRef
7.
Zurück zum Zitat Ding T, Xu J, Wang F, et al. High tumor-infiltrating macrophage density predicts poor prognosis in patients with primary hepatocellular carcinoma after resection. Hum Pathol. 2009;40(3):381–9.CrossRef Ding T, Xu J, Wang F, et al. High tumor-infiltrating macrophage density predicts poor prognosis in patients with primary hepatocellular carcinoma after resection. Hum Pathol. 2009;40(3):381–9.CrossRef
8.
Zurück zum Zitat Sumitomo R, Hirai T, Fujita M, Murakami H, Otake Y, Huang CL. PD-L1 expression on tumor-infiltrating immune cells is highly associated with M2 TAM and aggressive malignant potential in patients with resected non-small cell lung cancer. Lung Cancer. 2019;136:136–44.CrossRef Sumitomo R, Hirai T, Fujita M, Murakami H, Otake Y, Huang CL. PD-L1 expression on tumor-infiltrating immune cells is highly associated with M2 TAM and aggressive malignant potential in patients with resected non-small cell lung cancer. Lung Cancer. 2019;136:136–44.CrossRef
9.
Zurück zum Zitat Turley SJ, Cremasco V, Astarita JL. Immunological hallmarks of stromal cells in the tumour microenvironment. Nat Rev Immunol. 2015;15(11):669–82.CrossRef Turley SJ, Cremasco V, Astarita JL. Immunological hallmarks of stromal cells in the tumour microenvironment. Nat Rev Immunol. 2015;15(11):669–82.CrossRef
10.
Zurück zum Zitat Newman AM, Liu CL, Green MR, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12(5):453–7.CrossRef Newman AM, Liu CL, Green MR, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12(5):453–7.CrossRef
11.
Zurück zum Zitat Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Revs Clin Oncol. 2018;15(5):325.CrossRef Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Revs Clin Oncol. 2018;15(5):325.CrossRef
12.
Zurück zum Zitat Ayers M, Lunceford J, Nebozhyn M, et al. IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127(8):2930–40.CrossRef Ayers M, Lunceford J, Nebozhyn M, et al. IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127(8):2930–40.CrossRef
13.
Zurück zum Zitat Nielsen SR, Schmid MC. Macrophages as key drivers of cancer progression and metastasis. Mediat Inflamm. 2017;2017:9624760.CrossRef Nielsen SR, Schmid MC. Macrophages as key drivers of cancer progression and metastasis. Mediat Inflamm. 2017;2017:9624760.CrossRef
14.
Zurück zum Zitat Chen Y, Song Y, Du W, Gong L, Chang H, Zou Z. Tumor-associated macrophages: an accomplice in solid tumor progression. J Biomed Sci. 2019;26(1):78.CrossRef Chen Y, Song Y, Du W, Gong L, Chang H, Zou Z. Tumor-associated macrophages: an accomplice in solid tumor progression. J Biomed Sci. 2019;26(1):78.CrossRef
15.
Zurück zum Zitat Zhang J, Yan Y, Yang Y, et al. High infiltration of tumor-associated macrophages influences poor prognosis in human gastric cancer patients, associates with the phenomenon of EMT. Medicine. 2016;95(6):e2636.CrossRef Zhang J, Yan Y, Yang Y, et al. High infiltration of tumor-associated macrophages influences poor prognosis in human gastric cancer patients, associates with the phenomenon of EMT. Medicine. 2016;95(6):e2636.CrossRef
16.
Zurück zum Zitat Zhao Y, Ge X, Xu X, Yu S, Wang J, Sun L. Prognostic value and clinicopathological roles of phenotypes of tumour-associated macrophages in colorectal cancer. J Cancer Res Clin Oncol. 2019;145:3005–19.CrossRef Zhao Y, Ge X, Xu X, Yu S, Wang J, Sun L. Prognostic value and clinicopathological roles of phenotypes of tumour-associated macrophages in colorectal cancer. J Cancer Res Clin Oncol. 2019;145:3005–19.CrossRef
17.
Zurück zum Zitat Sjodahl G, Lovgren K, Lauss M, et al. Infiltration of CD3(+) and CD68(+) cells in bladder cancer is subtype specific and affects the outcome of patients with muscle-invasive tumors. Urol Oncol. 2014;32(6):791–7.CrossRef Sjodahl G, Lovgren K, Lauss M, et al. Infiltration of CD3(+) and CD68(+) cells in bladder cancer is subtype specific and affects the outcome of patients with muscle-invasive tumors. Urol Oncol. 2014;32(6):791–7.CrossRef
18.
Zurück zum Zitat Qiu S, Deng L, Liao X, et al. Tumor-associated macrophages promote bladder tumor growth through PI3K/AKT signal induced by collagen. Cancer Sci. 2019;110(7):2110–8.CrossRef Qiu S, Deng L, Liao X, et al. Tumor-associated macrophages promote bladder tumor growth through PI3K/AKT signal induced by collagen. Cancer Sci. 2019;110(7):2110–8.CrossRef
19.
Zurück zum Zitat Mitrofanova I, Zavyalova M, Telegina N, et al. Tumor-associated macrophages in human breast cancer parenchyma negatively correlate with lymphatic metastasis after neoadjuvant chemotherapy. Immunobiology. 2017;222(1):101–9.CrossRef Mitrofanova I, Zavyalova M, Telegina N, et al. Tumor-associated macrophages in human breast cancer parenchyma negatively correlate with lymphatic metastasis after neoadjuvant chemotherapy. Immunobiology. 2017;222(1):101–9.CrossRef
20.
Zurück zum Zitat Rakaee M, Busund LR, Jamaly S, et al. Prognostic value of macrophage phenotypes in resectable non-small cell lung cancer assessed by multiplex immunohistochemistry. Neoplasia. 2019;21(3):282–93.CrossRef Rakaee M, Busund LR, Jamaly S, et al. Prognostic value of macrophage phenotypes in resectable non-small cell lung cancer assessed by multiplex immunohistochemistry. Neoplasia. 2019;21(3):282–93.CrossRef
21.
Zurück zum Zitat Liu Z, Zhu Y, Xu L, et al. Tumor stroma-infiltrating mast cells predict prognosis and adjuvant chemotherapeutic benefits in patients with muscle invasive bladder cancer. Oncoimmunology. 2018;7(9):e1474317.CrossRef Liu Z, Zhu Y, Xu L, et al. Tumor stroma-infiltrating mast cells predict prognosis and adjuvant chemotherapeutic benefits in patients with muscle invasive bladder cancer. Oncoimmunology. 2018;7(9):e1474317.CrossRef
22.
Zurück zum Zitat Waks AG, Stover DG, Guerriero JL, et al. The immune microenvironment in hormone receptor-positive breast cancer before and after preoperative chemotherapy. Clin Cancer Res. 2019;25(15):4644–55.CrossRef Waks AG, Stover DG, Guerriero JL, et al. The immune microenvironment in hormone receptor-positive breast cancer before and after preoperative chemotherapy. Clin Cancer Res. 2019;25(15):4644–55.CrossRef
23.
Zurück zum Zitat Leow JJ, Martin-Doyle W, Rajagopal PS, et al. Adjuvant chemotherapy for invasive bladder cancer: a 2013 updated systematic review and meta-analysis of randomized trials. Eur Urol. 2014;66(1):42–54.CrossRef Leow JJ, Martin-Doyle W, Rajagopal PS, et al. Adjuvant chemotherapy for invasive bladder cancer: a 2013 updated systematic review and meta-analysis of randomized trials. Eur Urol. 2014;66(1):42–54.CrossRef
24.
Zurück zum Zitat Svatek RS, Shariat SF, Lasky RE, et al. The effectiveness of off-protocol adjuvant chemotherapy for patients with urothelial carcinoma of the urinary bladder. Clin Cancer Res. 2010;16(17):4461–7.CrossRef Svatek RS, Shariat SF, Lasky RE, et al. The effectiveness of off-protocol adjuvant chemotherapy for patients with urothelial carcinoma of the urinary bladder. Clin Cancer Res. 2010;16(17):4461–7.CrossRef
25.
Zurück zum Zitat Galsky MD, Stensland KD, Moshier E, et al. Effectiveness of adjuvant chemotherapy for locally advanced bladder cancer. J Clin Oncol. 2016;34(8):825–32.CrossRef Galsky MD, Stensland KD, Moshier E, et al. Effectiveness of adjuvant chemotherapy for locally advanced bladder cancer. J Clin Oncol. 2016;34(8):825–32.CrossRef
26.
Zurück zum Zitat Bellmunt J, Powles T, Vogelzang NJ. A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: the future is now. Cancer Treat Rev. 2017;54:58–67.CrossRef Bellmunt J, Powles T, Vogelzang NJ. A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: the future is now. Cancer Treat Rev. 2017;54:58–67.CrossRef
27.
Zurück zum Zitat Rouanne M, Roumiguie M, Houede N, et al. Development of immunotherapy in bladder cancer: present and future on targeting PD(L)1 and CTLA-4 pathways. World J Urol. 2018;36(11):1727–40.CrossRef Rouanne M, Roumiguie M, Houede N, et al. Development of immunotherapy in bladder cancer: present and future on targeting PD(L)1 and CTLA-4 pathways. World J Urol. 2018;36(11):1727–40.CrossRef
28.
Zurück zum Zitat Galsky MD, Wang H, Hahn NM, et al. Phase 2 trial of gemcitabine, cisplatin, plus ipilimumab in patients with metastatic urothelial cancer and impact of DNA damage response gene mutations on outcomes. Eur Urol. 2018;73(5):751–9.CrossRef Galsky MD, Wang H, Hahn NM, et al. Phase 2 trial of gemcitabine, cisplatin, plus ipilimumab in patients with metastatic urothelial cancer and impact of DNA damage response gene mutations on outcomes. Eur Urol. 2018;73(5):751–9.CrossRef
29.
Zurück zum Zitat Goodman AM, Kato S, Bazhenova L, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther. 2017;16(11):2598–608.CrossRef Goodman AM, Kato S, Bazhenova L, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther. 2017;16(11):2598–608.CrossRef
Metadaten
Titel
Stromal Tumor-Associated Macrophage Infiltration Predicts Poor Clinical Outcomes in Muscle-Invasive Bladder Cancer Patients
verfasst von
Shengming Jin, MD
Han Zeng, MD
Zhaopei Liu, MD
Kaifeng Jin, MD
Chunnan Liu, MD
Sen Yan, MD
Yanze Yu, MD
Runze You, MD
Hongyi Zhang, MD
Yuan Chang, MD
Le Xu, PhD
Jiejie Xu, MD, PhD
Zewei Wang, MD
Yu Zhu, PhD
Publikationsdatum
09.01.2022
Verlag
Springer International Publishing
Erschienen in
Annals of Surgical Oncology / Ausgabe 4/2022
Print ISSN: 1068-9265
Elektronische ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-021-11155-y

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