Abstract
Background
Muscle-invasive bladder cancer (MIBC) is an aggressive and heterogeneous malignancy. Tumor-associated macrophages (TAMs) are key infiltrating cell populations in the inflammatory microenvironment of malignant tumors including MIBC. It intrigues us to explore the clinical significance and immunoregulatory role of TAMs infiltration and polarization in MIBC.
Methods
A total of 141 patients with MIBC from Zhongshan Hospital and 391 patients with MIBC from The Cancer Genome Atlas (TCGA) database were included in this study. Moreover, 195 patients who received anti-PD-L1 therapy from the IMvigor210 trial were enrolled. Patients were categorized into three subtypes considering the infiltration level and polarization status of TAMs, denoted as TAMlow (Subtype I), TAMhigh&M2/M1low (Subtype II), and TAMhigh&M2/M1high (Subtype III).
Results
Subtype III suffered inferior prognosis, and Subtype II could benefit more from adjuvant chemotherapy (ACT). Subtype III was featured with increased pro-tumor cells and immunosuppressive cytokines, while Subtype II possessed more immunogenic cells infiltration with activated and tumoricidal properties. Subtype II and Subtype III presented basal/squamous-like characterization and showed additional prognostic merit beyond molecular classification. Subtype I exhibited elevated level of FGFR3 signature, while Subtype II had EGFR signaling activation and immunotherapeutic indication. Additionally, Subtype II patients were indeed highly sensitive to PD-L1 blockade therapy in IMvigor210 trial.
Conclusion
The infiltration and polarization status of TAMs shaped distinct immune microenvironment with predictive significance for survival outcome, ACT benefit, and PD-L1 blockade therapy sensitivity in MIBC. Immune classification based on TAMs polarization and infiltration might provide tools to tailor chemotherapy and immunotherapy.
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Data availability
All data generated that are relevant to the results presented in this article are included in this article. Other data that were not relevant for the results presented here are available from the corresponding author Prof. Xu upon reasonable request.
Abbreviations
- ACT:
-
Adjuvant chemotherapy
- AJCC:
-
American Joint Committee on Cancer
- CI:
-
Confidence interval
- CR:
-
Complete response
- CTLA-4:
-
Cytotoxic T-lymphocyte-associated protein 4
- EGFR:
-
Epidermal growth factor receptor
- FPKM:
-
Fragments Per Kilobase of transcript per Million mapped reads
- FGFR3:
-
Fibroblast growth factor 3
- GZMB:
-
Granzyme B
- HLA-DR:
-
Human leukocyte antigen DR
- HPF:
-
High power field
- HR:
-
Hazard ratio
- IC:
-
Immune cells
- ICIs:
-
Immune checkpoint inhibitors
- IFN-γ:
-
Interferon γ
- IHC:
-
Immunohistochemistry
- IL-10:
-
Interleukin 10
- LAG-3:
-
Lymphocyte-activation gene 3
- MIBC:
-
Muscle-invasive bladder cancer
- NAC:
-
Neoadjuvant chemotherapy
- NE:
-
Not evaluated
- NMIBC:
-
Non-muscle-invasive bladder cancer
- OS:
-
Overall survival
- PD:
-
Progressive disease
- PD-1:
-
Programmed cell death protein 1
- PD-L1:
-
Programmed cell death ligand protein 1
- PR:
-
Partial response
- PRF-1:
-
Perforin 1
- RC:
-
Radical cystectomy
- RFS:
-
Recurrence-free survival
- SD:
-
Stable disease
- TAMs:
-
Tumor-associated macrophages
- TC:
-
Tumor cells
- TCGA:
-
The Cancer Genome Atlas
- TGF-β:
-
Transforming growth factor β
- TIGIT:
-
T-cell immunoreceptor with Ig and ITIM domains
- TIM-3:
-
T-cell immunoglobulin and mucin‐domain containing‐3
- TMA:
-
Tissue microarray analysis
- TMB:
-
Tumor mutation burden
- TME:
-
Tumor microenvironment
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Acknowledgements
We thank Dr. Lingli Chen (Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China) and Dr. Yunyi Kong (Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China) for their excellent pathological technology help.
Funding
This study was funded by grants from National Natural Science Foundation of China (31770851, 81872082, 82002670, 82103408), Shanghai Municipal Natural Science Foundation (19ZR1431800), Shanghai Sailing Program (18YF1404500, 21YF1407000), Shanghai Municipal Commission of Health and Family Planning Program (201840168) and Fudan University Shanghai Cancer Center for Outstanding Youth Scholars Foundation (YJYQ201802). All these study sponsors have no roles in the study design, in the collection, analysis, and interpretation of data.
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M. Sun, H. Zeng, K. **, and Z. Liu involved in acquisition of data, analysis and interpretation of data, statistical analysis, and drafting of the manuscript; C. Liu, S. Yan, Y. Yu, R. You, H. Zhang, Y. Chang, Y. Wang, L. Liu, and Y. Zhu involved in technical and material support; J. Xu, L. Xu, and Z. Wang involved in study concept and design, analysis and interpretation of data, drafting of the manuscript, and obtained funding and study supervision. All authors read and approved the final manuscript.
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The study was approved by the Clinical Research Ethics Committee of Zhongshan Hospital, Fudan University, with the approval number Y2015-054. Written informed consent was obtained from each patient included and this study was performed under the Declaration of Helsinki. Signed informed consent was obtained from each patient.
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This study was approved by the Clinical Research Ethics Committee of Zhongshan Hospital, Fudan University (No. B2015-030). Written informed consent was obtained from each patient.
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Sun, M., Zeng, H., **, K. et al. Infiltration and Polarization of Tumor-associated Macrophages Predict Prognosis and Therapeutic Benefit in Muscle-Invasive Bladder Cancer. Cancer Immunol Immunother 71, 1497–1506 (2022). https://doi.org/10.1007/s00262-021-03098-w
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DOI: https://doi.org/10.1007/s00262-021-03098-w