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Infiltration and Polarization of Tumor-associated Macrophages Predict Prognosis and Therapeutic Benefit in Muscle-Invasive Bladder Cancer

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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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Author notes

  1. Mengmeng Sun, Han Zeng, Kaifeng Jin, Zhaopei Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China

    Mengmeng Sun, Han Zeng, Kaifeng Jin, Zhaopei Liu, Chunnan Liu, Sen Yan, Yanze Yu, Runze You, Hongyi Zhang & Jiejie Xu

  2. Department of Immunology, School of Medicine, Nantong University, Nantong, China

    Baoying Hu

  3. Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China

    Yuan Chang & Yu Zhu

  4. Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China

    Li Liu & Zewei Wang

  5. Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Le Xu

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  1. Mengmeng Sun
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Contributions

M. Sun, H. Zeng, K. Jin, 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.

Corresponding authors

Correspondence to Jiejie Xu, Le Xu or Zewei Wang.

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Conflict of interest

The authors declare that they have no competing interests.

Ethics approval

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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All authors provide their consent for publication.

Study approval

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., Jin, 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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