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Theranostics 2020; 10(15):7002-7014. doi:10.7150/thno.46176 This issue Cite

Research Paper

Macrophage correlates with immunophenotype and predicts anti-PD-L1 response of urothelial cancer

Dongqiang Zeng1*, Zilan Ye1*, Jiani Wu1, Rui Zhou1, Xinxiang Fan2, Gaofeng Wang3, Yiqiang Huang4, Jianhua Wu1, Huiying Sun1, Miaohong Wang1, Jianping Bin5, Yulin Liao5, Nailin Li6, Min Shi1, Wangjun Liao1✉

1. Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P. R. China;
2. Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China;
3. Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA;
4. Department of Urology, Daping Hospital, Army Medical University, Chongqing, P.R. China;
5. Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China;
6. Karolinska Institutet Department of Medicine-Solna, Clinical Pharmacology Group, Karolinska University Hospital-Solna, 171 76, Stockholm, Sweden.
*These authors contributed equally to this work.

✉ Corresponding author: Department of Oncology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, China. E-mail: nfyyliaowjcom (W. Liao)

Citation:
Zeng D, Ye Z, Wu J, Zhou R, Fan X, Wang G, Huang Y, Wu J, Sun H, Wang M, Bin J, Liao Y, Li N, Shi M, Liao W. Macrophage correlates with immunophenotype and predicts anti-PD-L1 response of urothelial cancer. Theranostics 2020; 10(15):7002-7014. doi:10.7150/thno.46176. https://www.thno.org/v10p7002.htm
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Abstract

Graphic abstract

Immune-checkpoint blockades (ICBs) have been routinely implemented to treat metastatic urothelial cancer (mUC), whereas robust biomarkers are urgently warranted. Herein, we explored latent promising biomarkers based on 348 pretreatment mUC samples from IMvigor210.

Methods: The genome, transcriptome, immunome, and metabolome were systemically analyzed using the external TCGA dataset for validation. Kaplan-Meier and ROC curve analyses were performed to estimate the predictive capacity of M1-macrophage infiltration. Chi-square/Spearman/Mann Whitney U test are used to determine its correlation to genetic, biochemical, and clinicopathological parameters.

Results: M1 frequency is a robust biomarker for predicting the prognosis and response to ICBs, which is non-inferior to tumor mutation burden (TMB) or tumor neoantigen burden (TNB), and exceeds CD8 T cells, T cell inflamed gene expression profile (GEP), and PD-L1 expression. Moreover, M1 infiltration is associated with immune phenotypes (AUC = 0.785) and is negatively correlated with immune exclusion. Additionally, transcriptomic analysis showed immune activation in the high-M1 subgroup, whereas it showed steroid and drug metabolism reprograming in the M1-deficient subset, which characterized the limited sensitivity to ICB therapy. Notably, investigation of the corresponding intrinsic genomic profiles highlighted the significance of TP53 and FGFR alterations.

Conclusions: M1 infiltration is a robust biomarker for immunotherapeutic response and immunophenotype determination in an mUC setting. Innate immunity activation involving macrophage polarization remodeling and anti-FGFR mutations may be promising strategies for synergy with anti-PD-L1 treatments and may help prolong the clinical survival of patients with mUC.

Keywords: immune checkpoint blockade, macrophage, immunophenotype, urothelial cancer

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APA
Zeng, D., Ye, Z., Wu, J., Zhou, R., Fan, X., Wang, G., Huang, Y., Wu, J., Sun, H., Wang, M., Bin, J., Liao, Y., Li, N., Shi, M., Liao, W. (2020). Macrophage correlates with immunophenotype and predicts anti-PD-L1 response of urothelial cancer. Theranostics, 10(15), 7002-7014. https://doi.org/10.7150/thno.46176.

ACS
Zeng, D.; Ye, Z.; Wu, J.; Zhou, R.; Fan, X.; Wang, G.; Huang, Y.; Wu, J.; Sun, H.; Wang, M.; Bin, J.; Liao, Y.; Li, N.; Shi, M.; Liao, W. Macrophage correlates with immunophenotype and predicts anti-PD-L1 response of urothelial cancer. Theranostics 2020, 10 (15), 7002-7014. DOI: 10.7150/thno.46176.

NLM
Zeng D, Ye Z, Wu J, Zhou R, Fan X, Wang G, Huang Y, Wu J, Sun H, Wang M, Bin J, Liao Y, Li N, Shi M, Liao W. Macrophage correlates with immunophenotype and predicts anti-PD-L1 response of urothelial cancer. Theranostics 2020; 10(15):7002-7014. doi:10.7150/thno.46176. https://www.thno.org/v10p7002.htm

CSE
Zeng D, Ye Z, Wu J, Zhou R, Fan X, Wang G, Huang Y, Wu J, Sun H, Wang M, Bin J, Liao Y, Li N, Shi M, Liao W. 2020. Macrophage correlates with immunophenotype and predicts anti-PD-L1 response of urothelial cancer. Theranostics. 10(15):7002-7014.

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