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Latency-associated peptide identifies therapeutically resistant muscle-invasive bladder cancer with poor prognosis

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Abstract

Background

Latency-associated peptide (LAP) was identified as crucial immune regulator in tumor microenvironment (TME) in recent researches. In this study, we aimed to estimate the predictive value of LAP expression for clinical survival and therapeutic response in muscle-invasive bladder cancer (MIBC).

Methods

Our study encompassed 140 MIBC patients from Zhongshan Hospital (ZSHS cohort), 401 patients from The Cancer Genome Atlas (TCGA cohort) and 195 patients received PDL1 blockade from IMvigor210 trial. Survival analyses were conducted through Kaplan–Meier curve and Cox regression model. LAP expression and its association with immune contexture were evaluated in ZSHS and TCGA cohort.

Results

We found that high intratumoral LAP+ cells infiltration anticipated inferior survival and adjuvant chemotherapy (ACT) response, and was closely related to an immunoevasive contexture with increased M2 macrophages, neutrophils and conspicuously a cluster of highly exhausted CD8+ T cells. The combinational analysis of LAP+ cells and CD8+ T cells infiltration stratified patients into distinct risk groups with implications for therapeutic sensitivity to PDL1 blockade and refinement of molecular classification in MIBC.

Conclusions

LAP expression was correlated with patients’ inferior prognosis, ACT-tolerance and an immunoevasive TME with exhausted CD8+ T cell infiltration, suggesting that LAP could serve as a promising therapeutic target in MIBC. Simultaneously, our novel TME classification based on LAP+ cells and CD8+ T cells infiltration and its potential in appraising PDL1 blockade application for MIBC patients deserved further validation.

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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 Dr. Xu upon reasonable request.

Abbreviations

ACT :

Adjuvant chemotherapy

AJCC :

American Joint Committee on Cancer

CI :

Confidence interval

FPKM :

Fragments per kilobase of exon model per million mapped fragments

GSEA :

Gene sets enrichment analysis

HR :

Hazard ratios

ICIs :

Immune checkpoint inhibitors

IHC :

Immunohistochemistry

LAP :

Latency-associated peptide

LVI :

Lymphatic vessel invasion

MIBC :

Muscle-invasive bladder cancer

NMIBC :

Non-muscle-invasive bladder cancer

OS :

Overall survival

RFS :

Recurrence-free survival

TCGA :

The Cancer Genome Atlas

TGF-β :

Transforming growth factor-β

TMA :

Tissue microarray

TME :

Tumor microenvironment

TNM :

Tumor–node–metastasis

ZSHS :

Zhongshan Hospital

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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, 81902556, 82002670), Shanghai Municipal Natural Science Foundation (19ZR1431800), Shanghai Sailing Program (18YF1404500, 19YF1427200, 21YF1407000), Shanghai Municipal Commission of Health and Family Planning Program (20174Y0042, 201840168, 20184Y0151) 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. Ruiting Ye, Han Zeng, Zhaopei Liu and Kaifeng Jin these authors contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Ruiting Ye, Yuan Chang & Yu Zhu

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

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

  3. Department of Urology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Yiwei Wang

  4. Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, 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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Contributions

R. Y, H. Z, Z. L and K. J were involved in acquisition of data, analysis and interpretation of data, statistical analysis and drafting of the manuscript; C. L, S. Y, Y. Y, R. Y, H. Z, Y. W, L. L and Y. Z helped in technical and material support; Y. C, J. X, L. X and Z. W contributed to study concept and design, analysis and interpretation of data, drafting of the manuscript, obtained funding and study supervision. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yuan Chang, Jiejie Xu, Le Xu or Zewei Wang.

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The authors declare no potential conflicts of interest.

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All authors provide their consent for publication.

Ethics approval and consent to participate

The study followed the Declaration of Helsinki and was approved by the Clinical Research Ethics Committee of Zhongshan Hospital. Signed informed consent was obtained from each patient.

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Supplementary information

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262_2021_2987_MOESM1_ESM.tif

Supplementary Figure 1. Patient cohort and IHC staining of LAP expression in MIBC. (A) Enrollment process of patients in ZSHS cohort and TCGA cohort. (B) Representative immunohistochemistry images of LAP+ cells. FFPE, Formalin-Fixed and Paraffin-Embedded (TIF 1220 kb)

262_2021_2987_MOESM2_ESM.tif

Supplementary Figure 2. Association of tumor immune microenvironment with LAP expression. (A) IHC evaluation of various immune cells between LAP+ cells low/high subgroups in ZSHS cohort. Mann–Whitney test was adopted (TIF 457 kb)

262_2021_2987_MOESM3_ESM.tif

Supplementary Figure 3. The survival benefit of CD8+ T cells infiltration is impaired by LAP expression. (A-B) Kaplan–Meier curve of OS according to LAP/TGFB1 expression and CD8+ T cells infiltration in TCGA cohort (A) and ZSHS cohort (B) (TIF 390 kb)

262_2021_2987_MOESM4_ESM.tif

Supplementary Figure 4. CD8+ T cells infiltration fails to predict prognosis in patients with high LAP/TGFB1 subgroup. (A-D) Kaplan–Meier curve of OS (A, C) and RFS (B, D) according to CD8+ cells infiltration in all patients (left), patients with low LAP/TGFB1 expression (middle) and patients with high LAP/TGFB1 expression (right) in ZSHS cohort (A, B) and TCGA cohort (C, D) (TIF 1642 kb)

262_2021_2987_MOESM5_ESM.tif

Supplementary Figure 5. Association of TME classification based on LAP expression and CD8+ T cells infiltration with clinical outcomes and molecular features in MIBC. (A-B) Kaplan-Meier curves of RFS between three clusters in ZSHS cohort (A) and TCGA cohort (B) by log-rank test. (C) Comparison of consensus molecular systems with three clusters in TCGA cohort by Chi-square test. (D) Kaplan–Meier curve of RFS by log-rank test in basal/squamous subtype between cluster II and cluster III patients in TCGA cohort (TIF 524 kb)

Supplementary Table 1. Patient characteristics and relationship with LAP/TGFB1 level (DOCX 72 kb)

Supplementary Table 2. Immunohistochemistry (IHC) antibodies (DOCX 55 kb)

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Ye, R., Zeng, H., Liu, Z. et al. Latency-associated peptide identifies therapeutically resistant muscle-invasive bladder cancer with poor prognosis. Cancer Immunol Immunother 71, 301–310 (2022). https://doi.org/10.1007/s00262-021-02987-4

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